Triazolone compounds as mPGES-1 inhibitors

ABSTRACT

The present disclosure is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, as mPGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.

RELATED APPLICATIONS

This application is the U.S. national phase of International ApplicationNo. PCT/IB2013/054752, filed Jun. 10, 2013, which claims the benefit ofIndian Provisional Application Nos. 1733/MUM/2012 filed on 15 Jun. 2012;3319/MUM/2012 filed on 19 Nov. 2012; and 387/MUM/2013 filed on 8 Feb.2013; and U.S. Provisional Application Nos. 61/668,146 filed on 5 Jul.2012; 61/735,679 filed on 11 Dec. 2012; and 61/792,225 filed on 15 Mar.2013.

TECHNICAL FIELD

The present application relates to triazolone compounds as mPGES-1inhibitors.

BACKGROUND OF THE INVENTION

There are many diseases or disorders that are inflammatory in theirnature. One of the major problems associated with existing treatments ofinflammatory conditions is inadequate efficacy and/or the prevalence ofside effects. Inflammatory diseases that affect the population includeasthma, inflammatory bowel disease, rheumatoid arthritis,osteoarthritis, rhinitis, conjunctivitis and dermatitis. Inflammation isalso a common cause of pain.

The enzyme cyclooxygenase (COX) converts arachidonic acid to an unstableintermediate, prostaglandin H₂ (PGH₂), which is further converted toother prostaglandins, including PGE₂, PGF_(2α), PGD₂, prostacyclin andthromboxane A₂. These arachidonic acid metabolites are known to havepronounced physiological and pathophysiological activity, includingpro-inflammatory effects. The COX enzyme exists in two forms, one thatis constitutively expressed in many cells and tissues (COX-1), andanother that in most cells and tissues is induced by pro-inflammatorystimuli, such as cytokines, during an inflammatory response (COX-2).

Among all prostaglandin metabolites, PGE₂ is particularly known to be astrong pro-inflammatory mediator, and is also known to induce fever andpain. Consequently, numerous drugs have been developed with a view toinhibiting the formation of PGE₂, including “NSAIDs” (non-steroidalanti-inflammatory drugs) and “coxibs” (selective COX-2 inhibitors).These drugs act predominantly by inhibition of COX-1 and/or COX-2,thereby reducing the formation of PGE₂. However, the inhibition of COXshas the disadvantage of reducing the formation of all metabolites ofPGH₂, thereby decreasing the beneficial properties of some of themetabolites. In view of this, drugs which act by inhibition of COXs aresuspected to cause adverse biological effects. For example, thenon-selective inhibition of COXs by NSAIDs may give rise togastrointestinal side-effects and affect platelet and renal function.Even the selective inhibition of COX-2 by coxibs, whilst reducing suchgastrointestinal side-effects, is believed to give rise tocardiovascular problems.

A combination of pharmacological, genetic and neutralizing antibodyapproaches demonstrates the importance of PGE₂ in inflammation. Theconversion of PGH₂ to PGE₂ by prostaglandin E synthases (PGES) may,therefore, represent a pivotal step in the propagation of inflammatorystimuli. There are two microsomal prostaglandin E synthases (mPGES-1 andmPGES-2), and one cytosolic prostaglandin E synthase (cPGES). mPGES-1 isan inducible PGES after exposure to pro-inflammatory stimuli. mPGES-1 isinduced in the periphery and CNS by inflammation, and representstherefore a target for acute and chronic inflammatory disorders. PGE₂ isa major prostanoid, produced from arachidonic acid liberated byphospholipases (PLAs), which drives the inflammatory processes.Arachidonic acid is transformed by the action of prostaglandin Hsynthase (PGH synthase, cycloxygenase) into PGH₂ which is a substratefor mPGES-1, the terminal enzyme transforming PGH₂ to thepro-inflammatory PGE₂.

Agents that are capable of inhibiting the action of mPGES-1, and thusreducing the formation of the specific arachidonic acid metabolite PGE₂,are beneficial in the treatment of inflammation. Further, agents thatare capable of inhibiting the action of the proteins involved in thesynthesis of the leukotrienes are also beneficial in the treatment ofasthma and COPD.

Blocking the formation of PGE₂ in animal models of inflammatory painresults in reduced inflammation, pain and fever response (Kojima et. al,The Journal of Immunology 2008, 180, 8361-6; Xu et. al., The Journal ofPharmacology and Experimental Therapeutics 2008, 326, 754-63). Inabdominal aortic aneurism, inflammation leads to connective tissuedegradation and smooth muscle apoptosis ultimately leading to aorticdilation and rupture. In animals lacking mPGES-1 a slower diseaseprogression and disease severity has been demonstrated (Wang et. al.,Circulation, 2008, 117, 1302-1309).

Several lines of evidence indicate that PGE₂ is involved in malignantgrowth. PGE₂ facilitates tumor progression by stimulation of cellularproliferation and angiogenesis and by modulation of immunosupression. Insupport of a role for PGE₂ in cancers, genetic deletion of mPGES-1 inmice suppresses intestinal tumourogenesis (Nakanishi et. al., CancerResearch 2008, 68(9), 3251-9). In human beings, mPGES-1 is alsoupregulated in cancers such as colorectal cancer (Schroder, Journal ofLipid Research 2006, 47, 1071-80).

Myositis is a chronic muscle disorder characterized by muscle weaknessand fatigue. Proinflammatory cytokines and prostanoids have beenimplicated in the development of myositis. In skeletal muscle tissuefrom patients suffering from myositis an increase in cyclooxygenases andmPGES-1 has been demonstrated, implicating mPGES-1 as a target fortreating this condition. (Korotkova, Annals of the Rheumatic Diseases2008, 67, 1596-1602).

In atherosclerosis, inflammation of the vasculature leads to atheromaformation that eventually may progress into infarction. In patients withcarotid atherosclerosis an increase in mPGES-1 in plaque regions hasbeen reported (Gomez-Hernandez Atherosclerosis 2006, 187, 139-49). In ananimal model of atherosclerosis, mice lacking the mPGES-1 receptor werefound to show a retarded atherogenesis and a concomitant reduction inmacrophage-derived foam cells together with an increase in vascularsmooth muscle cells (Wang, Proceedings of National Academy of Sciences2006, 103(39), 14507-12).

International Publication Nos. WO 2006/063466, WO 2007/059610, WO2010/034796, WO 2010/100249, WO 2012/055995, WO 2012/110860 and WO2013/038308 disclose numerous heterocyclic compounds which are stated tobe inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1)enzyme.

The present application is directed to compounds that act as inhibitorsof the mPGES-1 enzyme and, therefore, are useful for the treatment ofpain and inflammation in a variety of diseases or conditions.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a compound of formula(I)

or a pharmaceutically acceptable salt thereof,wherein,

ring A is selected from C₆₋₁₄aryl, 5-14 membered heteroaryl,C₃₋₁₂cycloalkyl and 3-15 membered heterocyclyl;

ring B is selected from C₆₋₁₄aryl, 5-14 membered heteroaryl,C₃₋₁₂cycloalkyl and 3-15 membered heterocyclyl;

each occurrence of L is independently selected from—(CR^(x)R^(y))_(q)NR^(x)C(O)—, and —(CR^(x)R^(y))_(q)NR^(x)S(O)₂—;

each occurrence of P is independently selected from—(CR^(x)R^(y))_(q)NR^(x)C(O)—, and —(CR^(x)R^(y))_(q)NR^(x)S(O)₂—;

each occurrence of Q is independently selected from C₁₋₈alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₈alkoxy, C₁₋₈alkoxyC₁₋₈alkyl,haloC₁₋₈alkyl, hydroxyC₁₋₈alkyl, carboxylC₁₋₈alkyl, C₃₋₁₂cycloalkyl,C₆₋₁₄aryl, C₆₋₁₄ arylC₁₋₈alkyl, 3-15 membered heterocyclyl, and 5-14membered heteroaryl;

each occurrence of W is independently selected from C₁₋₈alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₈alkoxy, C₁₋₈alkoxyC₁₋₈alkyl,haloC₁₋₈alkyl, hydroxyC₁₋₈ alkyl, carboxylC₁₋₈alkyl, C₃₋₁₂cycloalkyl,C₆₋₁₄aryl, C₆₋₁₄ arylC₁₋₈alkyl, 3-15 membered heterocyclyl, and 5-14membered heteroaryl;

each occurrence of R¹ is independently selected from halogen, cyano,C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxyC₁₋₈alkyl, haloC₁₋₈alkoxyC₁₋₈alkyl,haloC₁₋₈alkyl, haloC₁₋₈alkoxy, hydroxyC₁₋₈alkyl, C₃₋₁₂cycloalkyl,C₃₋₈cycloalkylC₁₋₈alkyl, C₆₋₁₄aryl, C₆₋₁₄arylC₁₋₈alkyl, C₆₋₁₄aryloxy,3-15 membered heterocyclyl, 3-15 membered heterocyclylC₁₋₈alkyl, 5-14membered heteroaryl, 5-14 membered heteroarylC₁₋₈alkyl, —C(O)NHR,—S(O)₂NHR, —NHC(O)R, —CH₂S(O)NHR and —C≡CR;

each occurrence of R² is independently selected from halogen, cyano,C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxyC₁₋₈alkyl, haloC₁₋₈alkyl,haloC₁₋₈alkoxy, hydroxyC₁₋₈alkyl, C₃₋₁₂cycloalkyl,C₃₋₈cycloalkylC₁₋₈alkyl, C₆₋₁₄aryl, C₆₋₁₄arylC₁₋₈alkyl, C₆₋₁₄aryloxy,3-15 membered heterocyclyl, 3-15 membered heterocyclylC₁₋₈alkyl, 5-14membered heteroaryl, 5-14 membered heteroarylC₁₋₈alkyl, —NHR, —C(O)NHR,—S(O)₂NHR, —NHC(O)R, —CH₂S(O)NHR and —C≡CR;

each occurrence of R is independently selected from C₁₋₈alkyl,C₃₋₁₂cycloalkyl, C₃₋₈cycloalkylC₁₋₈alkyl, C₆₋₁₄aryl, C₆₋₁₄arylC₁₋₈alkyl,3-15 membered heterocyclyl and 5-14 membered heteroaryl;

R³ is independently selected from hydrogen, C₁₋₈alkyl, C₃₋₁₂cycloalkyland C₆₋₁₄aryl;

at each occurrence, R^(x) and R^(y), which may be the same or different,are independently selected from hydrogen, C₁₋₈alkyl, C₃₋₁₂cycloalkyl andC₆₋₁₄aryl; or R^(x) and R^(y) together with the common atom to whichthey are attached, form a cyclic ring which is substituted orunsubstituted and wherein the cyclic ring optionally contains one ormore hetero atoms selected from O, N or S;

‘m’ is an integer ranging from 0 to 3, both inclusive;

‘n’ is an integer ranging from 0 to 3, both inclusive;

‘q’ is an integer ranging from 1 to 4, both inclusive;

‘s’ is an integer ranging from 0 to 1, both inclusive; and

‘t’ is an integer ranging from 0 to 1, both inclusive;

with the proviso that ‘m’ and ‘n’ are not ‘0’ simultaneously.

The compounds of formula (I) may involve one or more embodiments.Embodiments of formula (I) include compounds of formula (II), compoundsof formula (III) and compounds of formula (IV) as described hereinafter.It is to be understood that the embodiments below are illustrative ofthe present invention and are not intended to limit the claims to thespecific embodiments exemplified. It is also to be understood that theembodiments defined herein may be used independently or in conjunctionwith any definition of any other embodiment defined herein. Thus, theinvention contemplates all possible combinations and permutations of thevarious independently described embodiments. For example, the inventionprovides compounds of formula (I) as defined above, wherein R³ ishydrogen (according to an embodiment defined below), ‘n’ is 0, 1 or 2(according to another embodiment defined below), and ‘s’ is 1 and ‘t’ is0 (according to another embodiment defined below).

According to one embodiment, specifically provided are compounds offormula (I), in which ring A is C₆₋₁₄aryl (e.g. phenyl) or 5-14 memberedheteroaryl (e.g. pyridinyl).

According to another embodiment, specifically provided are compounds offormula (I), in which ring A is phenyl or pyridinyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ring B is C₆₋₁₄aryl (e.g. phenyl), 5-14membered heteroaryl (e.g. pyridinyl) or C₃₋₁₂cycloalkyl (e.g.cyclopentyl or cyclohexyl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ring B is phenyl, pyridinyl, cyclopentyl orcyclohexyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R³ is hydrogen.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R³ is C₁₋₈alkyl (e.g. methyl or ethyl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R³ is hydrogen, methyl or ethyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which P is —(CR^(x)R^(y))_(q)NR^(x)C(O)— or—(CR^(x)R^(y))_(q)NR^(x)S(O)₂—. In this embodiment, R^(x) and R^(y) areindependently selected from hydrogen and C₁₋₄alkyl (e.g. methyl orethyl), and ‘q’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which P is —CH₂NHC(O)— or —CH₂NHS(O)₂—.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which L is —(CR^(x)R^(y))_(q)NR^(x)C(O)— or—(CR^(x)R^(y))_(q)NR^(x)S(O)₂—. In this embodiment, R^(x) and R^(y) areindependently selected from hydrogen and C₁₋₄alkyl (e.g. methyl orethyl), and ‘q’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which L is —CH₂NHC(O)— or —CH₂NHS(O)₂—.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R¹ is independently selectedfrom cyano, halogen (e.g. F, Cl or Br), C₁₋₈alkyl (e.g. methyl),haloC₁₋₈alkyl (e.g. trifluoromethyl or difluoromethyl), C₁₋₈alkoxy (e.g.methoxy), haloC₁₋₈alkoxyC₁₋₈alkyl (e.g. (2,2,2-trifluoroethoxy)methyl),C₃₋₁₂cycloalkyl (e.g. cyclopropyl), 3-15 membered heterocyclylC₁₋₈alkyl(e.g. (pyrrolidin-1-yl)methyl), 5-14 membered heteroaryl (e.g.4-methylthiophenyl or 5-isopropyl-1,3,4-oxadiazol-2-yl), 5-14 memberedheteroarylC₁₋₈alkyl (e.g. (3,5-dimethyl-1H-pyrazol-1-yl)methyl),—S(O)₂NHR, —NHCOR, —CONHR and —C≡CR.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R¹ is independently selectedfrom —S(O)₂NHR, —NHCOR, —CONHR and —C≡CR. In this embodiment R isindependently selected from C₁₋₈alkyl (e.g. isopropyl or tert-butyl),C₃₋₁₂cycloalkyl (e.g. cyclopropyl) and C₆₋₁₄aryl (e.g.3,5-difluorophenyl, 4-(trifluoromethyl)phenyl,3-(trifluoromethyl)phenyl, 4-fluoro-3-(trifluoromethyl)phenyl,2-fluoro-5-(trifluoromethyl)phenyl, 2-chloro-4-methylphenyl,2,5-dichlorophenyl, 4-chloro-2-fluorophenyl, 3-chloro-2-fluorophenyl,2-chloro-4-(trifluoromethyl)phenyl, 3-(difluoromethyl)-4-fluorophenyl or3-(difluoromethyl)phenyl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R¹ is independently cyano,F, Cl, Br, methyl, trifluoromethyl, difluoromethyl, methoxy,(2,2,2-trifluoroethoxy)methyl, cyclopropyl, (pyrrolidin-1-yl)methyl,4-methylthiophenyl, 5-isopropyl-1,3,4-oxadiazol-2-yl,(3,5-dimethyl-1H-pyrazol-1-yl)methyl, —S(O)₂NHR, —NHCOR, —CONHR and—C≡CR. In this embodiment R is independently selected from isopropyl,tert-butyl, cyclopropyl, 3,5-difluorophenyl, 4-(trifluoromethyl)phenyl,3-(trifluoromethyl)phenyl, 4-fluoro-3-(trifluoromethyl)phenyl,2-fluoro-5-(trifluoromethyl)phenyl, 2-chloro-4-methylphenyl,2,5-dichlorophenyl, 4-chloro-2-fluorophenyl, 3-chloro-2-fluorophenyl,2-chloro-4-(trifluoromethyl)phenyl, 3-(difluoromethyl)-4-fluorophenyland 3-(difluoromethyl)phenyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R¹ is independently cyano,F, Cl, Br, methyl, trifluoromethyl, difluoromethyl, methoxy,(2,2,2-trifluoroethoxy)methyl, cyclopropyl, (pyrrolidin-1-yl)methyl,4-methylthiophenyl, 5-isopropyl-1,3,4-oxadiazol-2-yl,(3,5-dimethyl-1H-pyrazol-1-yl)methyl, N-cyclopropylsulfamoyl,4-(trifluoromethyl)benz amide, 3,5-difluorobenzamide,3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl,(2,5-dichlorophenyl)ethynyl, (4-chloro-2-fluorophenyl)ethynyl,(3-chloro-2-fluorophenyl)ethynyl,[2-chloro-4-(trifluoromethyl)phenyl]ethynyl,—CONH-[4-(trifluoromethyl)phenyl], —CONH-[3-(trifluoromethyl)phenyl],—CONH-[3-(difluoromethyl)phenyl],—CONH-[4-fluoro-3-(trifluoromethyl)phenyl],—CONH-[2-fluoro-5-(trifluoromethyl)phenyl] or—CONH-[2-chloro-4-methylphenyl].

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘n’ is 0, 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘n’ is 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R² is independently cyano,halogen (e.g. F, Cl or Br), C₁₋₈alkyl (e.g. methyl), haloC₁₋₈alkyl (e.g.trifluoromethyl), haloC₁₋₈alkoxy (e.g. trifluoromethoxy),C₃₋₁₂cycloalkyl (e.g. cyclopropyl), C₁₋₈alkoxy (e.g. methoxy), C₆₋₁₄aryl(e.g. 3-(trifluoromethoxy)phenyl), 5-14 membered heteroaryl (e.g.3-isopropyl-1,2,4-oxadiazol-5-yl,3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl,3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl,3-(3,5-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl,3-(3-fluoro-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl,4-methylthiophen-2-yl, 6-(trifluoromethyl)pyridin-3-yl,1,5,6-trimethyl-1H-benzo[d]imidazol-2-yl or5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl), —NHR, —C(O)NHR, —NHC(O)Ror —C≡CR.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R² is independently —NHR,—C(O)NHR or —NHC(O)R. In this embodiment R is independently selectedfrom C₁₋₈alkyl (e.g. isopropyl or tert-butyl), C₃₋₁₂cycloalkyl (e.g.cyclopropyl, 1-[2-(trifluoromethyl)phenyl]cyclopropyl, or1-[4-(trifluoromethyl)phenyl]cyclopropyl), C₃₋₈cycloalkylC₁₋₈alkyl (e.g.(cyclopropyl)methyl), C₆₋₁₄aryl (e.g. 2,5-dichlorophenyl,4-chloro-2-fluorophenyl, 3-chloro-2-fluorophenyl,4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl,2-(trifluoromethyl)phenyl, 3-(difluoromethyl)phenyl,2-chloro-4-(trifluoromethyl)phenyl, 4-fluoro-3-(trifluoromethyl)phenyl,2-fluoro-5-(trifluoromethyl)phenyl, 2-chloro-4-methylphenyl,2-fluoro-4-methylphenyl, 5-chloro-2-methylphenyl,3-(difluoromethyl)-4-fluorophenyl, 3-(difluoromethyl)phenyl,4-(methylsulfonyl)phenyl or2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl), C₆₋₁₄arylC₁₋₈alkyl(e.g. 2-(trifluoromethyl)benzyl or 4-fluoro-2-(trifluoromethyl)benzyl),and 5-14 membered heteroaryl (e.g. 6-fluorobenzo[d]thiazol-2-yl,1H-benzo[d]imidazol-2-yl, 5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl,6-fluoropyridin-3-yl, 5-(trifluoromethyl)pyridin-2-yl,3-chloropyridin-4-yl, 2-morpholinopyrimidin-5-yl, or6-(morpholin-4-yl)pyridin-3-yl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R² is —C≡CR. In thisembodiment R is independently selected from C₁₋₈alkyl (e.g. isopropyl ortert-butyl), C₃₋₁₂cycloalkyl (e.g. cyclopropyl), C₆₋₁₄aryl(2,5-dichlorophenyl, 4-chloro-2-fluorophenyl, 3-chloro-2-fluorophenyl,2-chloro-4-(trifluoromethyl)phenyl, or 2-(trifluoromethyl)phenyl) and5-14 membered heteroaryl (e.g. 6-fluoropyridin-3-yl,5-(trifluoromethyl)pyridin-2-yl, 3-chloropyridin-4-yl,2-morpholinopyrimidin-5-yl, or 6-(morpholin-4-yl)pyridin-3-yl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R² is —C≡CR. In thisembodiment R is independently selected from isopropyl, tert-butyl,cyclopropyl, 2,5-dichlorophenyl, 4-chloro-2-fluorophenyl,3-chloro-2-fluorophenyl, 2-chloro-4-(trifluoromethyl)phenyl,2-(trifluoromethyl)phenyl, 6-fluoropyridin-3-yl,5-(trifluoromethyl)pyridin-2-yl, 3-chloropyridin-4-yl,2-morpholinopyrimidin-5-yl, and 6-(morpholin-4-yl)pyridin-3-yl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R² is —NHR. In thisembodiment R is 3-(trifluoromethyl)phenyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R² is —NHC(O)R. In thisembodiment R is cyclopropyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R² is —C(O)NHR. In thisembodiment R is (cyclopropyl)methyl, 4-(trifluoromethyl)phenyl,3-(trifluoromethyl)phenyl, 3-(difluoromethyl)phenyl,4-fluoro-3-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl,2-chloro-4-methylphenyl, 2-fluoro-4-methylphenyl,5-chloro-2-methylphenyl, 3-(difluoromethyl)-4-fluorophenyl,3-(difluoromethyl)phenyl,2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl,2-(trifluoromethyl)benzyl, 4-fluoro-2-(trifluoromethyl)benzyl,1-[2-(trifluoromethyl)phenyl]cyclopropyl,1-[4-(trifluoromethyl)phenyl]cyclopropyl, 6-fluorobenzo[d]thiazol-2-yl,1H-benzo[d]imidazol-2-yl, 5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl or4-(methylsulfonyl)phenyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R² is independently cyano,F, Cl, Br, methyl, trifluoromethyl, trifluoromethoxy, methoxy,cyclopropyl, 3-(trifluoromethoxy)phenyl,3-isopropyl-1,2,4-oxadiazol-5-yl,3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl,3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl,3-(3,5-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl,3-(3-fluoro-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl,4-methylthiophen-2-yl, 6-(trifluoromethyl)pyridin-3-yl,1,5,6-trimethyl-1H-benzo[d]imidazol-2-yl,5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl,[3-(trifluoromethyl)phenyl]amine, cyclopropanecarboxamido,3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl,(2,5-dichlorophenyl)ethynyl, (4-chloro-2-fluorophenyl)ethynyl,(3-chloro-2-fluorophenyl)ethynyl,[2-chloro-4-(trifluoromethyl)phenyl]ethynyl,[2-(trifluoromethyl)phenyl]ethynyl, (6-fluoropyridin-3-yl)ethynyl,[5-(trifluoromethyl)pyridin-2-yl]ethynyl, (3-chloropyridin-4-yl)ethynyl,(2-morpholinopyrimidin-5-yl)ethynyl,[6-(morpholin-4-yl)pyridin-3-yl]ethynyl, C(O)NH-[(cyclopropyl)methyl],—CONH-[4-(trifluoromethyl)phenyl], —CONH-[3-(trifluoromethyl)phenyl],—CONH-[3-(difluoromethyl)phenyl],—CONH-[4-fluoro-3-(trifluoromethyl)phenyl],—CONH-[2-fluoro-5-(trifluoromethyl)phenyl],—CONH-[2-chloro-4-methylphenyl], —CONH-[2-fluoro-4-methylphenyl],—CONH-[5-chloro-2-methylphenyl],—CONH-[3-(difluoromethyl)-4-fluorophenyl],—CONH-[3-(difluoromethyl)phenyl],—CONH-{2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl},—CONH-[2-(trifluoromethyl)benzyl],—CONH-[4-fluoro-2-(trifluoromethyl)benzyl],—CONH-{1-[2-(trifluoromethyl)phenyl]cyclopropyl},—CONH-{1-[4-(trifluoromethyl)phenyl]cyclopropyl},—CONH-{6-fluorobenzo[d]thiazol-2-yl}, —CONH-{1H-benzo[d]imidazol-2-yl},—CONH-{5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl}, or—CONH-[4-(methylsulfonyl)phenyl].

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R² is —C(O)NHR or —C≡CR. Inthis embodiment R is cyclopropyl or cyclopropylmethyl, each of which maybe optionally substituted with one or more substituents selected fromhalogen (e.g. F, Cl or Br), C₁₋₈alkyl (e.g. methyl or ethyl), haloC₁₋₈alkyl (e.g. trifluoromethyl) and substituted phenyl (e.g.2-(trifluoromethyl)phenyl and 4-(trifluoromethyl)phenyl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R² is —C(O)NHR or —C≡CR. Inthis embodiment R is phenyl optionally substituted with one or moresubstituents selected from halogen (e.g. F, Cl or Br), C₁₋₈ alkyl (e.g.methyl or ethyl), haloC₁₋₈ alkyl (e.g. trifluoromethyl ordifluoromethyl), C₁₋₈ alkoxy (e.g. methoxy or ethoxy), haloC₁₋₈ alkoxy(e.g. trifluoromethoxy) and —SO₂R^(x′) (e.g. methylsulfonyl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R² is —C(O)NHR or —C≡CR. Inthis embodiment R is benzyl optionally substituted with one or moresubstituents selected from halogen (e.g. F, Cl or Br), C₁₋₈ alkyl (e.g.methyl or ethyl) and haloC₁₋₈ alkyl (e.g. trifluoromethyl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R² is —C≡CR. In thisembodiment R is pyridine or pyrimidine, each of which may be optionallysubstituted with one or more substituents selected from halogen (e.g. F,Cl or Br), C₁₋₈alkyl (e.g. methyl or ethyl), haloC₁₋₈alkyl (e.g.trifluoromethyl) and 5 membered heterocyclyl (e.g. morpholinyl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘m’ is 0, 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘m’ is 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of W is C₁₋₈alkyl (e.g.isopropyl or tert-butyl), haloC₁₋₈alkyl (e.g. trifluoromethyl or1-fluoro-2-methylpropan-2-yl), hydroxyC₁₋₈alkyl (e.g.1-hydroxy-2-methylpropan-2-yl) or C₃₋₁₂cycloalkyl (e.g. cyclopropyl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of W is C₁₋₄alkyl (e.g.isopropyl or tert-butyl), haloC₁₋₈alkyl (e.g. trifluoromethyl or1-fluoro-2-methylpropan-2-yl), hydroxyC₁₋₈alkyl (e.g.1-hydroxy-2-methylpropan-2-yl) or C₃₋₆cycloalkyl (e.g. cyclopropyl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of W is isopropyl, tert-butyl,trifluoromethyl, 1-fluoro-2-methylpropan-2-yl,1-hydroxy-2-methylpropan-2-yl or cyclopropyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of Q is C₁₋₈alkyl (e.g.isopropyl or tert-butyl), haloC₁₋₈alkyl (e.g. trifluoromethyl or1-fluoro-2-methylpropan-2-yl), C₁₋₈alkoxyC₁₋₈alkyl (e.g.1-methoxy-2-methylpropan-2-yl), hydroxyC₁₋₈alkyl (e.g.1-hydroxy-2-methylpropan-2-yl), C₃₋₁₂cycloalkyl (e.g. cyclopropyl,cyclobutyl or cyclopentyl), C₆₋₁₄aryl (e.g. 2-fluorophenyl), 3-15membered heterocyclyl (e.g. tetrahydrofuranyl, tetrahydrofuran-2-yl,(S)-tetrahydrofuran-2-yl or (R)-tetrahydrofuran-2-yl) or 5-14 memberedheteroaryl (e.g. isoxazolyl or 1-methyl-1H-imidazole-2-yl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of Q is isopropyl, tert-butyl,trifluoromethyl, 1-fluoro-2-methylpropan-2-yl,1-methoxy-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl,cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorophenyl, tetrahydrofuranyl,tetrahydrofuranyl, tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl,(R)-tetrahydrofuran-2-yl, isoxazolyl or 1-methyl-1H-imidazole-2-yl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘s’ is 0 and ‘t’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘s’ is 1 and ‘t’ is 0.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘s’ is 1 and ‘t’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘s’ is 0 and ‘t’ is 0.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R is independently selectedfrom C₁₋₈alkyl (e.g. isopropyl or tert-butyl), C₃₋₁₂cycloalkyl (e.g.cyclopropyl, 1-[2-(trifluoromethyl)phenyl]cyclopropyl, or1-[4-(trifluoromethyl)phenyl]cyclopropyl), C₃₋₈cycloalkylC₁₋₈alkyl (e.g.(cyclopropyl)methyl), C₆₋₁₄aryl (e.g. 2,5-dichlorophenyl,4-chloro-2-fluorophenyl, 3-chloro-2-fluorophenyl,4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl,2-(trifluoromethyl)phenyl, 3-(difluoromethyl)phenyl,2-chloro-4-(trifluoromethyl)phenyl, 4-fluoro-3-(trifluoromethyl)phenyl,2-fluoro-5-(trifluoromethyl)phenyl, 2-chloro-4-methylphenyl,2-fluoro-4-methylphenyl, 5-chloro-2-methylphenyl,3-(difluoromethyl)-4-fluorophenyl, 3-(difluoromethyl)phenyl,4-(methylsulfonyl)phenyl or2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl), C₆₋₁₄arylC₁₋₈alkyl(e.g. 2-(trifluoromethyl)benzyl or 4-fluoro-2-(trifluoromethyl)benzyl),and 5-14 membered heteroaryl (e.g. 6-fluorobenzo[d]thiazol-2-yl,1H-benzo[d]imidazol-2-yl, or 5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R is independently selectedfrom isopropyl, tert-butyl, cyclopropyl,1-[2-(trifluoromethyl)phenyl]cyclopropyl,1-[4-(trifluoromethyl)phenyl]cyclopropyl), (cyclopropyl)methyl,2,5-dichlorophenyl, 4-chloro-2-fluorophenyl, 3-chloro-2-fluorophenyl,4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl,2-(trifluoromethyl)phenyl, 3-(difluoromethyl)phenyl,2-chloro-4-(trifluoromethyl)phenyl, 4-fluoro-3-(trifluoromethyl)phenyl,2-fluoro-5-(trifluoromethyl)phenyl, 2-chloro-4-methylphenyl,2-fluoro-4-methylphenyl, 5-chloro-2-methylphenyl,3-(difluoromethyl)-4-fluorophenyl, 3-(difluoromethyl)phenyl,4-(methylsulfonyl)phenyl,2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl,2-(trifluoromethyl)benzyl, 4-fluoro-2-(trifluoromethyl)benzyl),6-fluorobenzo[d]thiazol-2-yl, 1H-benzo[d]imidazol-2-yl, or5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl.

According to an embodiment, specifically provided are compounds offormula (I) that exhibit an IC₅₀ value of less than 500 nM, preferablyless than 100 nM, more preferably less than 50 nM, with respect tomPGES-1 inhibition.

Further embodiments relating to groups R¹, R², m, n, s, t, P, L, Q and W(and groups defined therein) are described hereinafter in relation tothe compounds of formula (II), formula (III) and formula (IV). It is tobe understood that these embodiments are not limited to use inconjunction with formula (II), formula (III) or formula (IV), but applyindependently and individually to the compounds of formula (I). Forexample, in an embodiment described hereinafter, the inventionspecifically provides compounds of formula (II), formula (III) orformula (IV) in which ‘n’ is 0, 1 or 2, and consequently, there is alsoprovided a compound of formula (I) in which ‘n’ is 0, 1 or 2.

The invention also provides a compound of formula (II), which is anembodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (II)

or a pharmaceutically acceptable salt thereof,wherein,

X¹, X², X³ and X⁴ are each independently selected from CH and N;

each occurrence of L is independently selected from —CH₂NHC(O)— and—CH₂NHS(O)₂—;

each occurrence of P is independently selected from —CH₂NHC(O)— and—CH₂NHS(O)₂—;

each occurrence of Q is independently selected from C₁₋₈alkyl,haloC₁₋₈alkyl, C₁₋₈alkoxyC₁₋₈alkyl, hydroxyC₁₋₈alkyl, carboxylC₁₋₈alkyl,C₃₋₁₂cycloalkyl, C₆₋₁₄aryl, 3-15 membered heterocyclyl, and 5-14membered heteroaryl;

each occurrence of W is independently selected from C₁₋₈alkyl,haloC₁₋₈alkyl, C₁₋₈alkoxyC₁₋₈alkyl, hydroxyC₁₋₈alkyl, carboxylC₁₋₈alkyl,C₃₋₁₂cycloalkyl, C₆₋₁₄aryl, 3-15 membered heterocyclyl, and 5-14membered heteroaryl;

each occurrence of R¹ is independently selected from halogen, cyano,C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkoxyC₁₋₈alkyl, haloC₁₋₈alkyl,C₃₋₆cycloalkyl, 5 membered heterocyclylC₁₋₈alkyl, 5 membered heteroaryl,5 membered heteroarylC₁₋₈alkyl, and —C≡CR;

each occurrence of R² is independently selected from halogen, cyano,C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl, C₃₋₆cycloalkyl, 5 memberedheteroaryl, —C(O)NHR, —NHC(O)R, —S(O)₂NHR and —C≡CR;

each occurrence of R is independently selected from C₁₋₈alkyl,C₃₋₁₂cycloalkyl, and C₆₋₁₄aryl;

‘m’ is an integer ranging from 0 to 3, both inclusive;

‘n’ is an integer ranging from 0 to 3, both inclusive;

‘s’ is an integer ranging from 0 to 1, both inclusive; and

‘t’ is an integer ranging from 0 to 1, both inclusive;

with the provisos that (i) ‘s’ and ‘t’ are not ‘0’ simultaneously, and(ii) ‘m’ and ‘n’ are not ‘0’ simultaneously.

The compounds of formula (II) may involve one or more embodiments. It isto be understood that the embodiments below are illustrative of thepresent invention and are not intended to limit the claims to thespecific embodiments exemplified. It is also to be understood that theembodiments defined herein may be used independently or in conjunctionwith any definition of any other embodiment defined herein. Thus theinvention contemplates all possible combinations and permutations of thevarious independently described embodiments. For example, the inventionprovides compounds of formula (II) as defined above wherein X¹, X², X³and X⁴ are CH (according to an embodiment defined below), ‘m’ is 0, 1 or2 (according to another embodiment defined below), and ‘s’ is 0 and ‘t’is 1 (according to another embodiment defined below).

According to one embodiment, specifically provided are compounds offormula (II), in which X¹, X², X³ and X⁴ are CH.

According to another embodiment, specifically provided are compounds offormula (II), in which X¹ is N and X², X³ and X⁴ are CH.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which X² is N and X¹, X³ and X⁴ are CH.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which X³ is N and X¹, X² and X⁴ are CH.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of L is —CH₂NHC(O)—.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of P is —CH₂NHC(O)—.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of R¹ is independentlyselected from cyano, halogen (e.g. F, Cl or Br), C₁₋₈alkyl (e.g.methyl), haloC₁₋₈alkyl (e.g. trifluoromethyl or difluoromethyl),C₁₋₈alkoxy (e.g. methoxy), haloC₁₋₈alkoxyC₁₋₈alkyl (e.g.(2,2,2-trifluoroethoxy)methyl), C₃₋₆cycloalkyl (e.g. cyclopropyl), 5membered heterocyclylC₁₋₈alkyl (e.g. (pyrrolidin-1-yl)methyl), 5membered heteroaryl (e.g. 4-methylthiophenyl,5-isopropyl-1,3,4-oxadiazol-2-yl), 5 membered heteroarylC₁₋₈alkyl (e.g.(3,5-dimethyl-1H-pyrazol-1-yl)methyl) and —C≡CR.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of R¹ is independentlyselected from cyano, Cl, F, CHF₂, CF₃, OCH₃, CH₃,(2,2,2-trifluoroethoxy)methyl, cyclopropyl, (pyrrolidin-1-yl)methyl,4-methylthiophenyl, 5-isopropyl-1,3,4-oxadiazol-2-yl,(3,5-dimethyl-1H-pyrazol-1-yl)methyl and —C≡CR. In this embodiment R isisopropyl, tert-butyl, cyclopropyl, 4-chloro-2-fluorophenyl,3-chloro-2-fluorophenyl, 3-(trifluoromethyl)phenyl or2-chloro-4-(trifluoromethyl)phenyl.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of R¹ is independentlyselected from cyano, Cl, F, CHF₂, CF₃, OCH₃, CH₃,(2,2,2-trifluoroethoxy)methyl, cyclopropyl, (pyrrolidin-1-yl)methyl,4-methylthiophenyl, 5-isopropyl-1,3,4-oxadiazol-2-yl,(3,5-dimethyl-1H-pyrazol-1-yl)methyl, 3,3-dimethylbut-1-ynyl,2-cyclopropylethynyl, (2,5-dichlorophenyl)ethynyl,(4-chloro-2-fluorophenyl)ethynyl, (3-chloro-2-fluorophenyl)ethynyl,(3-(trifluoromethyl)phenyl)ethynyl and(2-chloro-4-(trifluoromethyl)phenyl)ethynyl.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of R¹ is independently cyano,Cl, F, CHF₂, CF₃, OCH₃, CH₃, (2,2,2-trifluoroethoxy)methyl, cyclopropyl,(pyrrolidin-1-yl)methyl, 4-methylthiophenyl,5-isopropyl-1,3,4-oxadiazol-2-yl, (3,5-dimethyl-1H-pyrazol-1-yl)methyl,3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl,(2,5-dichlorophenyl)ethynyl, (4-chloro-2-fluorophenyl)ethynyl,(3-chloro-2-fluorophenyl)ethynyl, (3-(trifluoromethyl)phenyl)ethynyl or(2-chloro-4-(trifluoromethyl)phenyl)ethynyl; and ‘n’ is 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which ‘n’ is 0, 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of R² is independentlyselected from cyano, halogen (e.g. F, Cl or Br), C₁₋₈alkyl (e.g.methyl), haloC₁₋₈alkyl (e.g. trifluoromethyl), C₁₋₈alkoxy (e.g.methoxy), 5 membered heteroaryl (e.g.3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl), —C(O)NHR, —NHC(O)R and —C≡CR.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of R² is independently—C(O)NHR, —NHC(O)R or —C≡CR. In this embodiment R is isopropyl,tert-butyl, cyclopropyl, 4-chloro-2-fluorophenyl,3-chloro-2-fluorophenyl, 3-(trifluoromethyl)phenyl,2-chloro-4-(trifluoromethyl)phenyl, 3-(difluoromethyl)-4-fluorophenyl or3-(difluoromethyl)phenyl).

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of R² is independently cyano,Cl, F, CH₃, CF₃, OCH₃, 3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl,cyclopropanecarboxamido, 3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl,—CONH-[3-(trifluoromethyl)phenyl],—CONH-[3-(difluoromethyl)-4-fluorophenyl] or—CONH-[3-(difluoromethyl)phenyl].

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of R² is independently cyano,Cl, F, CH₃, CF₃, OCH₃, 3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl,cyclopropanecarboxamido, 3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl,—CONH-[3-(trifluoromethyl)phenyl],—CONH-[3-(difluoromethyl)-4-fluorophenyl] or—CONH-[3-(difluoromethyl)phenyl]; and ‘m’ is 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which ‘m’ is 0, 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of W is C₁₋₈alkyl (e.g.isopropyl or tert-butyl), haloC₁₋₈alkyl (e.g. trifluoromethyl or1-fluoro-2-methylpropan-2-yl), hydroxyC₁₋₈alkyl (e.g.1-hydroxy-2-methylpropan-2-yl) or C₃₋₁₂cycloalkyl (e.g. cyclopropyl).

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of W is C₁₋₄alkyl (e.g.isopropyl or tert-butyl), haloC₁₋₈alkyl (e.g. trifluoromethyl or1-fluoro-2-methylpropan-2-yl), hydroxyC₁₋₈alkyl (e.g.1-hydroxy-2-methylpropan-2-yl) or C₃₋₆cycloalkyl (e.g. cyclopropyl).

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of W is isopropyl, tert-butyl,trifluoromethyl, 1-fluoro-2-methylpropan-2-yl,1-hydroxy-2-methylpropan-2-yl or cyclopropyl.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which W is isopropyl, tert-butyl, trifluoromethyl,1-fluoro-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl orcyclopropyl; ‘t’ is 1; and ‘s’ is 0.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of Q is C₁₋₈alkyl (e.g.isopropyl or tert-butyl), haloC₁₋₈alkyl (e.g. trifluoromethyl or1-fluoro-2-methylpropan-2-yl), C₁₋₈alkoxyC₁₋₈alkyl (e.g.1-methoxy-2-methylpropan-2-yl), hydroxyC₁₋₈alkyl (e.g.1-hydroxy-2-methylpropan-2-yl), C₃₋₁₂cycloalkyl (e.g. cyclopropyl,cyclobutyl or cyclopentyl), C₆₋₁₄aryl (e.g. 2-fluorophenyl), 3-15membered heterocyclyl (e.g. tetrahydrofuranyl, tetrahydrofuran-2-yl,(S)-tetrahydrofuran-2-yl or (R)-tetrahydrofuran-2-yl) or 5-14 memberedheteroaryl (e.g. isoxazolyl or 1-methyl-1H-imidazole-2-yl).

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of Q is isopropyl, tert-butyl,trifluoromethyl, 1-fluoro-2-methylpropan-2-yl,1-methoxy-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl,cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorophenyl, tetrahydrofuranyl,tetrahydrofuranyl, tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl,(R)-tetrahydrofuran-2-yl, isoxazolyl or 1-methyl-1H-imidazole-2-yl.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which Q is isopropyl, tert-butyl, trifluoromethyl,1-fluoro-2-methylpropan-2-yl, 1-methoxy-2-methylpropan-2-yl,1-hydroxy-2-methylpropan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl,2-fluorophenyl, tetrahydrofuranyl, tetrahydrofuranyl,tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl,(R)-tetrahydrofuran-2-yl, isoxazolyl or 1-methyl-1H-imidazole-2-yl; ‘s’is 1; and ‘t’ is 0.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which ‘s’ is 0 and ‘t’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which ‘s’ is 1 and ‘t’ is 0.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which ‘s’ is 1 and ‘t’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of R is independently selectedfrom C₁₋₈alkyl (e.g. isopropyl or tert-butyl), C₃₋₁₂cycloalkyl (e.g.cyclopropyl) and C₆₋₁₄aryl (e.g. 4-chloro-2-fluorophenyl,3-chloro-2-fluorophenyl, 3-(trifluoromethyl)phenyl,2-chloro-4-(trifluoromethyl)phenyl, 3-(difluoromethyl)-4-fluorophenyl or3-(difluoromethyl)phenyl).

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of R is phenyl optionallysubstituted with one or more substituents selected from Cl, F, CH₃,trifluoromethyl and difluoromethyl.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of R is independentlyisopropyl, tert-butyl, cyclopropyl, 4-chloro-2-fluorophenyl,3-chloro-2-fluorophenyl, 3-(trifluoromethyl)phenyl,2-chloro-4-(trifluoromethyl)phenyl, 3-(difluoromethyl)-4-fluorophenyl or3-(difluoromethyl)phenyl.

According to an embodiment, specifically provided are compounds offormula (II) that exhibit an IC₅₀ value of less than 500 nM, preferablyless than 100 nM, more preferably less than 50 nM with respect tomPGES-1 inhibition.

Further embodiments relating to groups R¹, R², m, n, s, t, P, L, Q and W(and groups defined therein) are described herein in relation to thecompounds of formula (I), formula (III) or formula (IV). It is to beunderstood that these embodiments are not limited to use in conjunctionwith formula (I), formula (III) or formula (IV), but apply independentlyand individually to the compounds of formula (II). For example, in anembodiment described hereinafter, the invention specifically providescompounds of formula (I), formula (III) or formula (IV) in which ‘n’ is0, 1 or 2, and consequently there is also provided a compound of formula(II) in which ‘n’ is 0, 1 or 2.

The invention also provides a compound of formula (III), which is anembodiment of a compound of formula (I).

Accordingly the invention provides the compound of formula (III)

or a pharmaceutically acceptable salt thereof,wherein,

X¹, X² and X³ are each independently selected from CH and N;

P is selected from —CH₂NHC(O)— and —CH₂NHS(O)₂—;

Q is selected from C₁₋₈alkyl, haloC₁₋₈alkyl, C₁₋₈alkoxyC₁₋₈alkyl,hydroxyC₁₋₈alkyl, carboxylC₁₋₈alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₄aryl, 3-15membered heterocyclyl, and 5-14 membered heteroaryl;

each occurrence of R¹ is independently selected from halogen, cyano,C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl and C₃₋₆cycloalkyl;

each occurrence of R² is independently selected from halogen, cyano,C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl, C₃₋₆cycloalkyl, 5 memberedheteroaryl, —C(O)NHR, —NHC(O)R, —S(O)₂NHR and —C≡CR;

each occurrence of R is independently selected from C₁₋₈alkyl,C₃₋₁₂cycloalkyl, and C₆₋₁₄aryl;

‘m’ is an integer ranging from 0 to 3, both inclusive; and

‘n’ is an integer ranging from 0 to 3, both inclusive;

with the proviso that ‘m’ and ‘n’ are not ‘0’ simultaneously.

The compounds of formula (III) may involve one or more embodiments. Itis to be understood that the embodiments below are illustrative of thepresent invention and are not intended to limit the claims to thespecific embodiments exemplified. It is also to be understood that theembodiments defined herein may be used independently or in conjunctionwith any definition of any other embodiment defined herein. Thus theinvention contemplates all possible combinations and permutations of thevarious independently described embodiments. For example, the inventionprovides compounds of formula (III) as defined above wherein X¹, X² andX³ are CH (according to an embodiment defined below), ‘m’ is 0, 1 or 2(according to another embodiment defined below) and ‘n’ is 0, 1 or 2(according to another embodiment defined below).

According to one embodiment, specifically provided are compounds offormula (III), in which X¹, X² and X³ are CH.

According to another embodiment, specifically provided are compounds offormula (III), in which X¹ is N and X² and X³ are CH.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which X² is N and X¹ and X³ are CH.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which X³ is N and X¹ and X² are CH.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which P is —CH₂NHC(O)—.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which each occurrence of R¹ is independentlyselected from cyano, halogen (e.g. F, Cl or Br), C₁₋₈alkyl (e.g.methyl), haloC₁₋₈alkyl (e.g. trifluoromethyl or difluoromethyl),C₁₋₈alkoxy (e.g. methoxy) and C₃₋₆cycloalkyl (e.g. cyclopropyl).

According to yet another embodiment, specifically provided are compoundsof formula (III), in which each occurrence of R¹ is independentlyselected from cyano, Cl, F, CHF₂, CF₃, OCH₃, CH₃ and cyclopropyl.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which each occurrence of R¹ is independently cyano,Cl, F, CHF₂, CF₃, OCH₃, CH₃ or cyclopropyl; and ‘n’ is 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which ‘n’ is 0, 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which each occurrence of R² is independentlyselected from cyano, halogen (e.g. F, Cl or Br), C₁₋₈alkyl (e.g.methyl), haloC₁₋₈alkyl (e.g. trifluoromethyl), C₁₋₈alkoxy (e.g.methoxy), 5 membered heteroaryl (e.g.3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl), —C(O)NHR, —NHC(O)R and —C≡CR.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which each occurrence of R² is independently—C(O)NHR, —NHC(O)R and —C≡CR. In this embodiment R is isopropyl,tert-butyl, cyclopropyl, 4-chloro-2-fluorophenyl,3-chloro-2-fluorophenyl, 3-(trifluoromethyl)phenyl,2-chloro-4-(trifluoromethyl)phenyl, 3-(difluoromethyl)-4-fluorophenyl or3-(difluoromethyl)phenyl.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which each occurrence of R² is independently cyano,Cl, F, CH₃, CF₃, OCH₃, 3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl,cyclopropanecarboxamido, 3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl,—CONH-[3-(trifluoromethyl)phenyl],—CONH-[3-(difluoromethyl)-4-fluorophenyl] or—CONH-[3-(difluoromethyl)phenyl].

According to yet another embodiment, specifically provided are compoundsof formula (III), in which R² is independently cyano, Cl, F, CH₃, CF₃,OCH₃, 3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl, cyclopropanecarboxamido,3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl,—CONH-[3-(trifluoromethyl)phenyl],—CONH-[3-(difluoromethyl)-4-fluorophenyl] or—CONH-[3-(difluoromethyl)phenyl]; and ‘m’ is 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which ‘m’ is 0, 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which Q is C₁₋₈alkyl (e.g. isopropyl ortert-butyl), haloC₁₋₈alkyl (e.g. trifluoromethyl or1-fluoro-2-methylpropan-2-yl), C₁₋₈alkoxyC₁₋₈alkyl (e.g.1-methoxy-2-methylpropan-2-yl), hydroxyC₁₋₈alkyl (e.g.1-hydroxy-2-methylpropan-2-yl), C₃₋₁₂cycloalkyl (e.g. cyclopropyl,cyclobutyl or cyclopentyl), C₆₋₁₄aryl (e.g. 2-fluorophenyl), 3-15membered heterocyclyl (e.g. tetrahydrofuranyl, tetrahydrofuran-2-yl,(S)-tetrahydrofuran-2-yl or (R)-tetrahydrofuran-2-yl) or 5-14 memberedheteroaryl (e.g. isoxazolyl or 1-methyl-1H-imidazole-2-yl).

According to yet another embodiment, specifically provided are compoundsof formula (III), in which Q is isopropyl, tert-butyl, trifluoromethyl,1-fluoro-2-methylpropan-2-yl, 1-methoxy-2-methylpropan-2-yl,1-hydroxy-2-methylpropan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl,2-fluorophenyl, tetrahydrofuranyl, tetrahydrofuranyl,tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl,(R)-tetrahydrofuran-2-yl, isoxazolyl or 1-methyl-1H-imidazole-2-yl.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which each occurrence of R is independentlyselected from C₁₋₈alkyl (e.g. isopropyl or tert-butyl), C₃₋₁₂cycloalkyl(e.g. cyclopropyl) and C₆₋₁₄aryl (e.g. 4-chloro-2-fluorophenyl,3-chloro-2-fluorophenyl, 3-(trifluoromethyl)phenyl,2-chloro-4-(trifluoromethyl)phenyl, 3-(difluoromethyl)-4-fluorophenyl or3-(difluoromethyl)phenyl).

According to yet another embodiment, specifically provided are compoundsof formula (III), in which each occurrence of R is phenyl optionallysubstituted with one or more substituents selected from Cl, F, CH₃,trifluoromethyl and difluoromethyl.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which each occurrence of R is independentlyisopropyl, tert-butyl, cyclopropyl, 4-chloro-2-fluorophenyl,3-chloro-2-fluorophenyl, 3-(trifluoromethyl)phenyl,2-chloro-4-(trifluoromethyl)phenyl, 3-(difluoromethyl)-4-fluorophenyl or3-(difluoromethyl)phenyl.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which:

each R¹ is, independently, cyano, Cl, F, CHF₂, CF₃, OCH₃, CH₃ orcyclopropyl;

each R² is, independently, cyano, Cl, F, CH₃, CF₃ or OCH₃;

P is —CH₂NHC(O)—;

‘m’ is 1 or 2;

‘n’ is 0, 1 or 2; and

Q is isopropyl, tert-butyl, trifluoromethyl,1-fluoro-2-methylpropan-2-yl, 1-methoxy-2-methylpropan-2-yl,1-hydroxy-2-methylpropan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl,2-fluorophenyl, tetrahydrofuranyl, tetrahydrofuranyl,tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl,(R)-tetrahydrofuran-2-yl, isoxazolyl or 1-methyl-1H-imidazole-2-yl.

According to an embodiment, specifically provided are compounds offormula (III) which exhibit an IC₅₀ value of less than 500 nM,preferably less than 100 nM, more preferably less than 50 nM withrespect to mPGES-1 inhibition.

Further embodiments relating to groups R¹, R², m, n, s, t, P, L, Q and W(and groups defined therein) are described herein in relation to thecompounds of formula (I), formula (II) or formula (IV). It is to beunderstood that these embodiments are not limited to use in conjunctionwith formula (I), formula (II) or formula (IV), but apply independentlyand individually to the compounds of formula (III). For example, in anembodiment described hereinafter, the invention specifically providescompounds of formula (I), formula (II) or formula (IV) in which ‘n’ is0, 1 or 2, and consequently there is also provided a compound of formula(III) in which ‘n’ is 0, 1 or 2.

The invention also provides a compound of formula (IV), which is anembodiment of a compound of formula (I).

Accordingly the invention provides the compound of formula (IV)

or a pharmaceutically acceptable salt thereof,wherein,

L is selected from —CH₂NHC(O)— and —CH₂NHS(O)₂—;

W is selected from C₁₋₈alkyl, haloC₁₋₈alkyl, C₁₋₈alkoxyC₁₋₈alkyl,hydroxyC₁₋₈alkyl, carboxylC₁₋₈alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₄aryl, 3-15membered heterocyclyl, and 5-14 membered heteroaryl;

each occurrence of R¹ is independently selected from halogen, cyano,C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkoxyC₁₋₈alkyl, haloC₁₋₈alkyl,C₃₋₆cycloalkyl, 5 membered heterocyclylC₁₋₈alkyl, 5 membered heteroaryl,5 membered heteroarylC₁₋₈alkyl, and —C≡CR;

each occurrence of R² is independently selected from halogen, cyano,C₁₋₈alkyl, C₁₋₈alkoxy and haloC₁₋₈alkyl;

each occurrence of R is independently selected from C₁₋₈alkyl,C₃₋₁₂cycloalkyl, and C₆₋₁₄aryl;

‘m’ is an integer ranging from 0 to 3, both inclusive; and

‘n’ is an integer ranging from 0 to 3, both inclusive; with the provisothat ‘m’ and ‘n’ are not ‘0’ simultaneously.

The compounds of formula (IV) may involve one or more embodiments. It isto be understood that the embodiments below are illustrative of thepresent invention and are not intended to limit the claims to thespecific embodiments exemplified. It is also to be understood that theembodiments defined herein may be used independently or in conjunctionwith any definition of any other embodiment defined herein. Thus theinvention contemplates all possible combinations and permutations of thevarious independently described embodiments. For example, the inventionprovides compounds of formula (IV) as defined above wherein L is—CH₂NHC(O)— (according to an embodiment defined below), ‘m’ is 0, 1 or 2(according to another embodiment defined below), and ‘n’ is 0, 1 or 2(according to another embodiment defined below).

According to one embodiment, specifically provided are compounds offormula (IV), in which L is —CH₂NHC(O)—.

According to another embodiment, specifically provided are compounds offormula (IV), in which each occurrence of R¹ is independently selectedfrom cyano, halogen (e.g. F, Cl or Br), C₁₋₈alkyl (e.g. methyl),haloC₁₋₈alkyl (e.g. trifluoromethyl or difluoromethyl), C₁₋₈alkoxy (e.g.methoxy), haloC₁₋₈alkoxyC₁₋₈alkyl (e.g. (2,2,2-trifluoroethoxy)methyl),5 membered heterocyclylC₁₋₈alkyl (e.g. (pyrrolidin-1-yl)methyl), 5membered heteroaryl (e.g. 4-methylthiophenyl,5-isopropyl-1,3,4-oxadiazol-2-yl), 5 membered heteroarylC₁₋₈alkyl (e.g.(3,5-dimethyl-1H-pyrazol-1-yl)methyl) and —C≡CR.

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which each occurrence of R¹ is independentlyselected from cyano, Cl, F, CHF₂, CF₃, OCH₃, CH₃,(2,2,2-trifluoroethoxy)methyl, (pyrrolidin-1-yl)methyl,4-methylthiophenyl, 5-isopropyl-1,3,4-oxadiazol-2-yl,(3,5-dimethyl-1H-pyrazol-1-yl)methyl and —C≡CR. In this embodiment R isisopropyl, tert-butyl, cyclopropyl, 4-chloro-2-fluorophenyl,3-chloro-2-fluorophenyl, 3-(trifluoromethyl)phenyl or2-chloro-4-(trifluoromethyl)phenyl.

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which each occurrence of R¹ is independentlyselected from cyano, Cl, F, CHF₂, CF₃, OCH₃, CH₃,(2,2,2-trifluoroethoxy)methyl, (pyrrolidin-1-yl)methyl,4-methylthiophenyl, 5-isopropyl-1,3,4-oxadiazol-2-yl,(3,5-dimethyl-1H-pyrazol-1-yl)methyl, 3,3-dimethylbut-1-ynyl,2-cyclopropylethynyl, (2,5-dichlorophenyl)ethynyl,(4-chloro-2-fluorophenyl)ethynyl, (3-chloro-2-fluorophenyl)ethynyl,(3-(trifluoromethyl)phenyl)ethynyl and(2-chloro-4-(trifluoromethyl)phenyl)ethynyl.

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which each occurrence of R¹ is independently cyano,Cl, F, CHF₂, CF₃, OCH₃, CH₃, (2,2,2-trifluoroethoxy)methyl,(pyrrolidin-1-yl)methyl, 4-methylthiophenyl,5-isopropyl-1,3,4-oxadiazol-2-yl, (3,5-dimethyl-1H-pyrazol-1-yl)methyl,3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl,(2,5-dichlorophenyl)ethynyl, (4-chloro-2-fluorophenyl)ethynyl,(3-chloro-2-fluorophenyl)ethynyl, (3-(trifluoromethyl)phenyl)ethynyl or(2-chloro-4-(trifluoromethyl)phenyl)ethynyl; and ‘n’ is 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which ‘n’ is 0, 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which each occurrence of R² is independentlyselected from cyano, halogen (e.g. F, Cl or Br), C₁₋₈alkyl (e.g.methyl), haloC₁₋₈alkyl (e.g. trifluoromethyl) and C₁₋₈alkoxy (e.g.methoxy).

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which each occurrence of R² is independently cyano,Cl, F, CH₃, CF₃ or OCH₃.

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which each occurrence of R² is independently cyano,Cl, F, CH₃, CF₃ or OCH₃; and ‘m’ is 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which ‘m’ is 0, 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which W is C₁₋₈alkyl (e.g. isopropyl or tert-butyl),haloC₁₋₈alkyl (e.g. trifluoromethyl or 1-fluoro-2-methylpropan-2-yl),hydroxyC₁₋₈alkyl (e.g. 1-hydroxy-2-methylpropan-2-yl) or C₃₋₁₂cycloalkyl(e.g. cyclopropyl).

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which W is C₁₋₄alkyl (e.g. isopropyl or tert-butyl),haloC₁₋₈alkyl (e.g. trifluoromethyl or 1-fluoro-2-methylpropan-2-yl),hydroxyC₁₋₈alkyl (e.g. 1-hydroxy-2-methylpropan-2-yl) or C₃₋₆cycloalkyl(e.g. cyclopropyl).

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which W is isopropyl, tert-butyl, trifluoromethyl,1-fluoro-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl orcyclopropyl.

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which each occurrence of R is independently selectedfrom C₁₋₈alkyl (e.g. isopropyl or tert-butyl), C₃₋₁₂cycloalkyl (e.g.cyclopropyl) and C₆₋₁₄aryl (e.g. 4-chloro-2-fluorophenyl,3-chloro-2-fluorophenyl, 3-(trifluoromethyl)phenyl,2-chloro-4-(trifluoromethyl)phenyl, 3-(difluoromethyl)-4-fluorophenyl or3-(difluoromethyl)phenyl).

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which each occurrence of R is phenyl optionallysubstituted with one or more substituents selected from Cl, F,trifluoromethyl and difluoromethyl.

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which each occurrence of R is independentlyisopropyl, tert-butyl, cyclopropyl, 4-chloro-2-fluorophenyl,3-chloro-2-fluorophenyl, 3-(trifluoromethyl)phenyl,2-chloro-4-(trifluoromethyl)phenyl, 3-(difluoromethyl)-4-fluorophenyl or3-(difluoromethyl)phenyl).

According to yet another embodiment, specifically provided are compoundsof formula (IV), in which:

each occurrence of R¹ is independently Cl, F, CHF₂, CF₃, OCH₃, CH₃,3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl,(2,5-dichlorophenyl)ethynyl, (4-chloro-2-fluorophenyl)ethynyl,3-chloro-2-fluorophenyl)ethynyl, 3-(trifluoromethyl)phenyl)ethynyl or2-chloro-4-(trifluoromethyl)phenyl)ethynyl;

each occurrence of R² is independently Cl, F, CH₃, CF₃ or OCH₃;

L is —CH₂NHC(O)—;

‘m’ is 1 or 2;

‘n’ is 0, 1 or 2; and

W is isopropyl, tert-butyl, trifluoromethyl,1-fluoro-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl orcyclopropyl.

According to an embodiment, specifically provided are compounds offormula (IV) that exhibit an IC₅₀ value of less than 500 nM, preferablyless than 100 nM, more preferably less than 50 nM with respect tomPGES-1 inhibition.

It should be understood that the formulas (I), (II), (III) and (IV),structurally encompass all geometrical isomers, stereoisomers,enantiomers and diastereomers, N-oxides, and pharmaceutically acceptablesalts that may be contemplated from the chemical structure of the generadescribed herein.

Compounds of the present invention include the compounds in Examples1-192.

According to an embodiment, the compounds of formula (I) (wherein R³ isH), formula (II), formula (III) or formula (IV) structurally encompassall tautomeric forms whether such tautomer exists in equilibrium orpredominantly in one form. Such tautomeric form may be different or thesame when the compound is bound to the mPGES-1 enzyme.

The present application also provides a pharmaceutical composition thatincludes at least one compound described herein and at least onepharmaceutically acceptable excipient (such as a pharmaceuticallyacceptable carrier or diluent). Preferably, the pharmaceuticalcomposition comprises a therapeutically effective amount of at least onecompound described herein. The compounds described herein may beassociated with a pharmaceutically acceptable excipient (such as acarrier or a diluent) or be diluted by a carrier, or enclosed within acarrier which can be in the form of a capsule, sachet, paper or othercontainer.

The compounds and pharmaceutical compositions of the present inventionare useful for inhibiting the activity of mPGES-1, which is related to avariety of disease states.

The present invention further provides a method of inhibiting mPGES-1 ina subject in need thereof by administering to the subject one or morecompounds described herein in an amount effective to cause inhibition ofsuch receptor.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The terms “halogen” or “halo” means fluorine (fluoro), chlorine(chloro), bromine (bromo), or iodine (iodo).

The term “alkyl” refers to a hydrocarbon chain radical that includessolely carbon and hydrogen atoms in the backbone, containing nounsaturation, having from one to eight carbon atoms (i.e. C₁₋₈alkyl),and which is attached to the rest of the molecule by a single bond,e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl,n-pentyl, and 1,1-dimethylethyl (t-butyl). The term “C₁₋₆ alkyl” refersto an alkyl chain having 1 to 6 carbon atoms. The term “C₁₋₆alkyl”refers to an alkyl chain having 1 to 4 carbon atoms. Unless set forth orrecited to the contrary, all alkyl groups described or claimed hereinmay be straight chain or branched, substituted or unsubstituted.

The term “alkenyl” refers to a hydrocarbon chain containing from 2 to 10carbon atoms (i.e. C₂₋₁₀alkenyl) and including at least onecarbon-carbon double bond. Non-limiting examples of alkenyl groupsinclude ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Unless set forth orrecited to the contrary, all alkenyl groups described or claimed hereinmay be straight chain or branched, substituted or unsubstituted.

The term “alkynyl” refers to a hydrocarbyl radical having at least onecarbon-carbon triple bond, and having 2 to about 12 carbon atoms (withradicals having 2 to about 10 carbon atoms being preferred i.e.C₂₋₁₀alkynyl). Non-limiting examples of alkynyl groups include ethynyl,propynyl, and butynyl. Unless set forth or recited to the contrary, allalkynyl groups described or claimed herein may be straight chain orbranched, substituted or unsubstituted.

The term “alkoxy” denotes an alkyl group attached via an oxygen linkageto the rest of the molecule (i.e. C₁₋₈ alkoxy). Representative examplesof such groups are —OCH₃ and —OC₂H₅. Unless set forth or recited to thecontrary, all alkoxy groups described or claimed herein may be straightchain or branched, substituted or unsubstituted.

The term “alkoxyalkyl” or “alkyloxyalkyl” refers to an alkoxy oralkyloxy group as defined above directly bonded to an alkyl group asdefined above (i.e. C₁₋₈alkoxyC₁₋₈alkyl or C₁₋₈alkyloxyC₁₋₈alkyl).Example of such alkoxyalkyl moiety includes, but are not limited to,—CH₂OCH₃ and —CH₂OC₂H₅. Unless set forth or recited to the contrary, allalkoxyalkyl groups described herein may be straight chain or branched,substituted or unsubstituted.

The term “haloalkyl” refers to at least one halo group (selected from F,Cl, Br or I), linked to an alkyl group as defined above (i.e.haloC₁₋₈alkyl). Examples of such haloalkyl moiety include, but are notlimited to, trifluoromethyl, difluoromethyl and fluoromethyl groups.Unless set forth or recited to the contrary, all haloalkyl groupsdescribed herein may be straight chain or branched, substituted orunsubstituted.

The term “haloalkoxy” refers to an alkoxy group substituted with one ormore halogen atoms (i.e. haloC₁₋₈alkoxy). Examples of “haloalkoxy”include but are not limited to fluoromethoxy, difluoromethoxy,trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy,pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and1-bromoethoxy. Unless set forth or recited to the contrary, allhaloalkoxy groups described herein may be straight chain or branched,substituted or unsubstituted.

The term “haloalkoxyalkyl” refers to haloalkoxy group as defined abovedirectly bonded to an alkyl group as defined above (i.e.haloC₁₋₈alkoxyC₁₋₈alkyl). Examples of “haloC₁₋₈alkoxyC₁₋₈alkyl” includebut are not limited to (2,2,2-trifluoroethoxy)methyl or(2,2-difluoroethoxy)methyl. Unless set forth or recited to the contrary,all haloalkoxyalkyl groups described herein may be straight chain orbranched, substituted or unsubstituted.

The term “hydroxyalkyl” refers to an alkyl group as defined abovewherein one to three hydrogen atoms on different carbon atoms is/arereplaced by hydroxyl groups (i.e. hydroxyC₁₋₈alkyl). Examples ofhydroxyalkyl moieties include, but are not limited to —CH₂OH, —C₂H₄OHand —CH(OH)C₂H₄OH. Unless set forth or recited to the contrary, allhydroxyalkyl groups described herein may be straight chain or branched,substituted or unsubstituted.

The term “carboxyl” means the group —COOH.

The term “carboxylalkyl” refers to C₁₋₈alkyl group as defined abovewherein at least one of the hydrogen atoms of the C₁₋₈alkyl group isreplaced by a carboxyl group (i.e. “carboxylC₁₋₈alkyl”). Examples ofcarboxylalkyl moieties include, but are not limited to carboxylmethyl(—CH₂—COOH), carboxylethyl (—CH₂—CH₂—COOH), carboxylisopropyl(—C(CH₃)₂—COOH) and carboxyltertbutyl (—C(CH₃)₂CH₂—COOH). Unless setforth or recited to the contrary, all carboxylalkyl groups describedherein may be straight chain or branched, substituted or unsubstituted.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of 3 to about 12 carbon atoms, (i.e. C₃₋₁₂cycloalkyl). Examplesof monocyclic cycloalkyl include but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicycliccycloalkyl groups include, but are not limited to, perhydronapthyl,adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclicgroups, e.g., spiro(4,4)non-2-yl. The term “C₃₋₆cycloalkyl” refers tothe cyclic ring having 3 to 6 carbon atoms. Unless set forth or recitedto the contrary, all cycloalkyl groups described or claimed herein maybe substituted or unsubstituted.

The term “cycloalkylalkyl” refers to a non-aromatic cyclicring-containing radical having 3 to about 8 carbon atoms directlyattached to an alkyl group (i.e. C₃₋₈cycloalkylC₁₋₈alkyl). Thecycloalkylalkyl group may be attached to the main structure at anycarbon atom in the alkyl group that results in the creation of a stablestructure. Non-limiting examples of such groups includecyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless setforth or recited to the contrary, all cycloalkylalkyl groups describedor claimed herein may be substituted or unsubstituted.

The term “cycloalkenyl” refers to a cyclic ring-containing radicalhaving 3 to about 8 carbon atoms with at least one carbon-carbon doublebond, (i.e. C₃₋₈cycloalkenyl). Examples of “cycloalkenyl” include butare not limited to cyclopropenyl, cyclobutenyl, and cyclopentenyl.Unless set forth or recited to the contrary, all cycloalkenyl groupsdescribed or claimed herein may be substituted or unsubstituted.

The term “cycloalkenylalkyl” refers to a non-aromatic cyclicring-containing radical having 3 to about 8 carbon atoms with at leastone carbon-carbon double bond, directly attached to an alkyl group,(i.e. C₃₋₈cycloalkenylC₁₋₈alkyl). Unless set forth or recited to thecontrary, all cycloalkenylalkyl groups described or claimed herein maybe substituted or unsubstituted.

The term “aryl” refers to an aromatic radical having 6 to 14 carbonatoms (i.e. C₆₋₁₄aryl), including monocyclic, bicyclic and tricyclicaromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl,and biphenyl. Unless set forth or recited to the contrary, all arylgroups described or claimed herein may be substituted or unsubstituted.

The term “aryloxy” refers to an aryl group as defined above attached viaan oxygen linkage to the rest of the molecule (i.e. C₆₋₁₄aryloxy).Examples of aryloxy moieties include, but are not limited to phenoxy andnaphthoxy. Unless set forth or recited to the contrary, all aryloxygroups described herein may be substituted or unsubstituted.

The term “arylalkyl” refers to an aryl group as defined above directlybonded to an alkyl group as defined above, i.e. C₆₋₁₄arylC₁₋₈alkyl, suchas —CH₂C₆H₅ and —C₂H₄C₆H₅. Unless set forth or recited to the contrary,all arylalkyl groups described or claimed herein may be substituted orunsubstituted.

The term “heterocyclic ring” or “heterocyclyl” unless otherwisespecified refers to substituted or unsubstituted non-aromatic 3 to 15membered ring radical (i.e. 3 to 15 membered heterocyclyl) whichconsists of carbon atoms and from one to five hetero atoms selected fromnitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radicalmay be a mono-, bi- or tricyclic ring system, which may include fused,bridged or spiro ring systems, and the nitrogen, phosphorus, carbon,oxygen or sulfur atoms in the heterocyclic ring radical may beoptionally oxidized to various oxidation states. In addition, thenitrogen atom may be optionally quaternized; also, unless otherwiseconstrained by the definition the heterocyclic ring or heterocyclyl mayoptionally contain one or more olefinic bond(s). Examples of suchheterocyclic ring radicals include, but are not limited to azepinyl,azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl,dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl,isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl,octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl,pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl,tetrahydroisquinolyl, tetrahydrofuryl or tetrahydrofuranyl,tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl,thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. Unless set forthor recited to the contrary, all heterocyclyl groups described or claimedherein may be substituted or unsubstituted.

The term “heterocyclylalkyl” refers to a heterocyclic ring radicaldirectly bonded to an alkyl group (i.e. 3 to 15 memberedheterocyclylC₁₋₈alkyl). Unless set forth or recited to the contrary, allheterocyclylalkyl groups described or claimed herein may be substitutedor unsubstituted.

The term “heteroaryl” unless otherwise specified refers to substitutedor unsubstituted 5 to 14 membered aromatic heterocyclic ring radicalwith one or more heteroatom(s) independently selected from N, O or S(i.e. 5 to 14 membered heteroaryl). The heteroaryl may be a mono-, bi-or tricyclic ring system. Examples of such heteroaryl ring radicalsinclude, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl,indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl,thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl,benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl,quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl,quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl,acridinyl, phenazinyl and phthalazinyl. Unless set forth or recited tothe contrary, all heteroaryl groups described or claimed herein may besubstituted or unsubstituted.

The term “heteroarylalkyl” refers to a heteroaryl ring radical directlybonded to an alkyl group (i.e. 5 to 14 membered heterarylC₁₋₈alkyl).Unless set forth or recited to the contrary, all heteroarylalkyl groupsdescribed or claimed herein may be substituted or unsubstituted.

Unless otherwise specified, the term “substituted” as used herein refersto substitution with any one or any combination of the followingsubstituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio(═S), substituted or unsubstituted alkyl, substituted or unsubstitutedhaloalkyl, substituted or unsubstituted hydroxyl alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted haloalkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted amino, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted heterocyclic ring, substituted orunsubstituted guanidine, —COOR^(x′), —C(O)R^(x′), —C(S)R^(x′),—C(O)NR^(x′)R^(y′), —C(O)ONR^(x′)R^(y′), —NR^(x′)CONR^(y′)R^(z′),—N(R^(x′)) SOR^(y′), —N(R^(x′))SO₂R^(y′), —(═N—N(R^(x′))R^(y′)),—NR^(x′)C(O)OR^(y′), —NR^(x′)R^(y′), —NR^(x′)C(O)R^(y′),—NR^(x′)C(S)R^(y′), —NR^(x′)C(S)NR^(y′)R^(z′), —SONR^(x′)R^(y′),—SO₂NR^(x′)R^(y′), —OR^(x′), —OC(O)NR^(y′)R^(z′), —OC(O)OR^(y′),—OC(O)R^(x′), —OC(O)NR^(x′)R^(y′), —SR^(x′), —SOR^(x′), —SO₂R^(x′), and—ONO₂, wherein each occurrence of R^(x′), R^(y′) and R^(z′) areindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substitutedor unsubstituted amino, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted heterocyclylalkyl, substitutedor unsubstituted heteroarylalkyl, and substituted or unsubstitutedheterocyclic ring. The substituents in the aforementioned “substituted”groups cannot be further substituted. For example, when the substituenton “substituted alkyl” is “substituted aryl”, the substituent on“substituted aryl” can be unsubstituted alkenyl but cannot be“substituted alkenyl”.

The term “pharmaceutically acceptable salt” includes salts prepared frompharmaceutically acceptable bases or acids including inorganic ororganic bases and inorganic or organic acids. Examples of such saltsinclude, but are not limited to, acetate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate,carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate,edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate),palmitate, pantothenate, phosphate, diphosphate, polygalacturonate,salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide and valerate. Examples of salts derivedfrom inorganic bases include, but are not limited to, aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,manganic, mangamous, potassium, sodium, and zinc.

The term “treating” or “treatment” of a state, disorder or conditionincludes: (a) preventing or delaying the appearance of clinical symptomsof the state, disorder or condition developing in a subject that may beafflicted with or predisposed to the state, disorder or condition butdoes not yet experience or display clinical or subclinical symptoms ofthe state, disorder or condition; (b) inhibiting the state, disorder orcondition, i.e., arresting or reducing the development of the disease orat least one clinical or subclinical symptom thereof; or (c) relievingthe disease, i.e., causing regression of the state, disorder orcondition or at least one of its clinical or subclinical symptoms.

The term “subject” includes mammals (especially humans) and otheranimals, such as domestic animals (e.g., household pets including catsand dogs) and non-domestic animals (such as wildlife).

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a subject for treating a state, disorder orcondition, is sufficient to effect such treatment. The “therapeuticallyeffective amount” may vary depending on the compound, the disease andits severity and the age, weight, physical condition and responsivenessof the subject to be treated.

The sensation of pain can be triggered by any number of physical orchemical stimuli and the sensory neurons which mediate the response tothis harmful stimulus are termed as “nociceptors”. Nociceptors areprimary sensory afferent (C and δ fibers) neurons that are activated bya wide variety of noxious stimuli including chemical, mechanical,thermal, and proton (pH<6) modalities. Nociceptors are the nerves whichsense and respond to parts of the body which suffer from damage. Theysignal tissue irritation, impending injury, or actual injury. Whenactivated, they transmit pain signals (via the peripheral nerves as wellas the spinal cord) to the brain.

The term “chronic pain” usually refers to pain which persists for 3months or longer and can lead to significant changes in a patient'spersonality, lifestyle, functional ability and overall quality of life.Chronic pain can be classified as either nociceptive or neuropathic.Nociceptive pain includes tissue injury-induced pain and inflammatorypain such as that associated with arthritis. Neuropathic pain is causedby damage to the sensory nerves of the peripheral or central nervoussystem and is maintained by aberrant somatosensory processing. The painis typically well localized, constant, and often with an aching orthrobbing quality. Visceral pain is the subtype of nociceptive pain thatinvolves the internal organs. It tends to be episodic and poorlylocalized. Nociceptive pain is usually time limited, meaning when thetissue damage heals, the pain typically resolves (arthritis is a notableexception in that it is not time limited).

Pharmaceutical Compositions

The compounds of the invention are typically administered in the form ofa pharmaceutical composition. Such compositions can be prepared usingprocedures known in the pharmaceutical art and comprise at least onecompound of the invention. The pharmaceutical composition of the presentpatent application comprises one or more compounds described herein andone or more pharmaceutically acceptable excipients. Typically, thepharmaceutically acceptable excipients are approved by regulatoryauthorities or are generally regarded as safe for human or animal use.The pharmaceutically acceptable excipients include, but are not limitedto, carriers, diluents, glidants and lubricants, preservatives,buffering agents, chelating agents, polymers, gelling agents,viscosifying agents, and solvents.

Examples of suitable carriers include, but are not limited to, water,salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil,gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate,sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia,stearic acid, lower alkyl ethers of cellulose, silicic acid, fattyacids, fatty acid amines, fatty acid monoglycerides and diglycerides,fatty acid esters, and polyoxyethylene.

The pharmaceutical composition may also include one or morepharmaceutically acceptable auxiliary agents, wetting agents, suspendingagents, preserving agents, buffers, sweetening agents, flavoring agents,colorants or any combination of the foregoing.

The pharmaceutical compositions may be in conventional forms, forexample, capsules, tablets, solutions, suspensions, injectables orproducts for topical application. Further, the pharmaceuticalcomposition of the present invention may be formulated so as to providea desired release profile.

Administration of the compounds of the invention, in pure form or in anappropriate pharmaceutical composition, can be carried out using any ofthe accepted routes of administration of pharmaceutical compositions.The route of administration may be any route which effectivelytransports the active compound of the patent application to theappropriate or desired site of action. Suitable routes of administrationinclude, but are not limited to, oral, nasal, buccal, dermal,intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous,intraurethral, intramuscular, or topical.

Solid oral formulations include, but are not limited to, tablets,capsules (soft or hard gelatin), dragees (containing the activeingredient in powder or pellet form), troches and lozenges.

Liquid formulations include, but are not limited to, syrups, emulsions,and sterile injectable liquids, such as suspensions or solutions.

Topical dosage forms of the compounds include ointments, pastes, creams,lotions, powders, solutions, eye or ear drops, and impregnateddressings, and may contain appropriate conventional additives such aspreservatives, solvents to assist drug penetration.

The pharmaceutical compositions of the present patent application may beprepared by conventional techniques, e.g., as described in Remington:The Science and Practice of Pharmacy, 20^(th) Ed., 2003 (LippincottWilliams & Wilkins).

Suitable doses of the compounds for use in treating the diseases anddisorders described herein can be determined by those skilled in therelevant art. Therapeutic doses are generally identified through a doseranging study in humans based on preliminary evidence derived fromanimal studies. Doses are generally sufficient to result in a desiredtherapeutic benefit without causing unwanted side effects. Mode ofadministration, dosage forms, and suitable pharmaceutical excipients canalso be well used and adjusted by those skilled in the art. All changesand modifications are envisioned within the scope of the present patentapplication.

In another embodiment, the present invention relates to a pharmaceuticalcomposition comprising a compound as described herein, a secondtherapeutic agent, and optionally a pharmaceutically-acceptableexcipient. In one embodiment, the pharmaceutical composition includes acompound as described herein and a second therapeutic agent, whereineach of the compound described herein and the second therapeutic agentis formulated in admixture with a pharmaceutically-acceptable excipient.

Methods of Treatment

Compounds of the present invention are particularly useful because theymay inhibit the activity of prostaglandin E synthases (and particularlymicrosomal prostaglandin E synthase-1 (mPGES-1)), i.e., they prevent,inhibit, or suppress the action of mPGES-1 or a complex of which themPGES-1 enzyme forms a part, and/or may elicit mPGES-1 modulatingeffect. Compounds of the invention are thus useful in the treatment ofthose conditions treatable by inhibition of a PGES, and particularlymPGES-1.

Compounds of the invention are thus expected to be useful in thetreatment of inflammation. The term “inflammation” will be understood bythose skilled in the art to include any condition characterized by alocalized or a systemic protective response, which may be elicited byphysical trauma, infection, chronic diseases, such as those mentionedhereinbefore, and/or chemical and/or physiological reactions to externalstimuli (e.g. as part of an allergic response). Any such response, whichmay serve to destroy, dilute or sequester both the injurious agent andthe injured tissue, may be manifest by, for example, heat, swelling,pain, redness, dilation of blood vessels and/or increased blood flow.

The term “inflammation” is also understood to include any inflammatorydisease, disorder or condition per se, any condition that has aninflammatory component associated with it, and/or any conditioncharacterized by inflammation as a symptom, including, inter alia,acute, chronic, ulcerative, specific, allergic, infection by pathogens,immune reactions due to hypersensitivity, entering foreign bodies,physical injury, and necrotic inflammation, and other forms ofinflammation known to those skilled in the art. The term thus alsoincludes, for the purposes of this invention, inflammatory pain, paingenerally and/or fever.

The compounds of the present invention may also be useful in thetreatment of asthma, chronic obstructive pulmonary disease, pulmonaryfibrosis, inflammatory bowel disease, irritable bowel syndrome,inflammatory pain, chronic pain, acute pain, fever, migraine, headache,low back pain, fibromyalgia, myofascial disorders, viral infections(e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS),bacterial infections, fungal infections, dysmenorrhea, burns, surgicalor dental procedures, malignancies (e.g. breast cancer, colon cancer,and prostate cancer), hyperprostaglandin E syndrome, classic Barttersyndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenilearthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis,rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemiclupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis,conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis,eczema, psoriasis, stroke, diabetes mellitus, neurodegenerativedisorders such as Alzheimer's disease and multiple sclerosis, autoimmunediseases, allergic disorders, rhinitis, ulcers, mild to moderatelyactive ulcerative colitis, familial adenomatous polyposis, coronaryheart disease, sarcoidosis and any other disease with an inflammatorycomponent.

Compounds of the invention may also have effects that are not linked toinflammatory mechanisms, such as in the reduction of bone loss in asubject. Conditions that may be mentioned in this regard includeosteoporosis, osteoarthritis, Paget's disease and/or periodontaldiseases.

By virtue of the mPGES-1 inhibitory activity of compounds of the presentinvention, the compounds are useful for the relief of pain, fever andinflammation of a variety of conditions including rheumatic fever,symptoms associated with influenza or other viral infections, commoncold, low back and neck pain, dysmenorrhea, headache, migraine (acuteand prophylactic treatment), toothache, sprains and strains, myositis,neuralgia, synovitis, arthritis, including rheumatoid arthritis,juvenile rheumatoid arthritis, degenerative joint diseases(osteoarthritis), acute gout and ankylosing spondylitis, acute, subacuteand chronic musculoskeletal pain syndromes such as bursitis, burns,injuries, and pain following surgical (post-operative pain) and dentalprocedures as well as the preemptive treatment of surgical pain. Thepain may be mild pain, moderate pain, severe pain, musculoskeletal pain,complex regional pain syndrome, neuropathic pain, back pain such asacute visceral pain, neuropathies, acute trauma, chemotherapy-inducedmononeuropathy pain states, polyneuropathy pain states (such as diabeticperipheral neuropathy & chemotherapy induced neuropathy), autonomicneuropathy pain states, pheriphaeral nervous system (PNS) lesion orcentral nervous system (CNS) lesion or disease related pain states,polyradiculopathies of cervical, lumbar or sciatica type, cauda equinasyndrome, piriformis syndrome, paraplegia, quadriplegia, pain statesrelated to various Polyneuritis conditions underlying variousinfections, chemical injuries, radiation exposure, underlying disease ordeficiency conditions (such as beriberi, vitamin deficiencies,hypothyroidism, porphyria, cancer, HIV, autoimmune disease such asmultiple sclerosis and spinal-cord injury, fibromyalgia, nerve injury,ischaemia, neurodegeneration, stroke, post stroke pain, inflammatorydisorders, oesophagitis, gastroeosophagal reflux disorder (GERD),irritable bowel syndrome, inflammatory bowel disease, pelvichypersensitivity, urinary incontinence, cystitis, stomach duodenalulcer, muscle pain, pain due to colicky and referred pain. Compounds ofthe present invention may also be useful for the treatment or preventionof endometriosis, hemophilic arthropathy and Parkinson's disease.

Compounds of the present invention will also inhibit prostanoid-inducedsmooth muscle contraction by preventing the synthesis of contractileprostanoids and hence may be of use in the treatment of dysmenorrhea,premature labor and asthma.

In addition, the compounds of the present invention may inhibit cellularneoplastic transformations and metastic tumor growth and hence can beused in the treatment of cancer, and pain associated with cancer.Furthermore, the present invention provides preferred embodiments of themethods and uses as described herein, in which cancer includes AcuteLymphoblastic Leukemia, Acute Myeloid Leukemia, Adolescents Cancer,Adrenocortical Carcinoma, Anal Cancer, Appendix Cancer, Astrocytomas,Atypical Teratoid, Basal Cell Carcinoma, Bile Duct Cancer, Extrahepatic,Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumor, BreastCancer, Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumor, Carcinomaof Unknown Primary, Cardiac (Heart) Tumors, Central Nervous Systemtumors, Cervical Cancer, Childhood Cancers, Chordoma, ChronicLymphocytic Leukemia, Chronic Myelogenous Leukemia, ChronicMyeloproliferative Disorders, Colon Cancer, Colorectal Cancer,Craniopharyngioma, Cutaneous T-Cell Lymphoma, Duct Bile Extrahepaticcancer, Ductal Carcinoma In Situ, Embryonal Tumors, Central NervousSystem cancer, Endometrial Cancer, Ependymoma, Esophageal Cancer,Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor,Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer,Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, Gall bladderCancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor,Gastrointestinal Stromal Tumors, Germ Cell Tumor, GestationalTrophoblastic Tumor, Glioma, Hairy Cell Leukemia, Head and Neck Cancer,Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, LangerhansCell, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma,Islet Cell Tumors, Pancreatic Neuroendocrine Tumors, Kaposi Sarcoma,Kidney cancer, Langerhans Cell Histiocytosis, Laryngeal Cancer, AcuteLymphoblastic Leukemia, Acute Myeloid Leukemia, Chronic LymphocyticLeukemia, Chronic Myelogenous Leukemia, Hairy Cell Leukemia, Lip andOral Cavity Cancer, Liver Cancer, Lobular Carcinoma In Situ, LungCancer, AIDS-Related Lymphoma, Cutaneous T-Cell Lymphoma, HodgkinLymphoma, Non-Hodgkin Lymphoma, Primary Central Nervous System (CNS)Lymphoma, Macroglobulinemia, Waldenström, Male Breast Cancer, MalignantFibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Merkel CellCarcinoma, Mesothelioma, Malignant, Metastatic Squamous Neck Cancer withOccult Primary, Midline Tract Carcinoma Involving NUT Gene, MouthCancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/PlasmaCell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes,Myelodysplastic/Myeloproliferative Neoplasms, Myelogenous Leukemia,Chronic, Myeloid Leukemia Acute, Multiple Myeloma, ChronicMyeloproliferative Disorders, Nasal Cavity and Paranasal Sinus Cancer,Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-SmallCell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and,Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma ofBone, Ovarian Cancer, Pancreatic Cancer, Papillomatosis, Paraganglioma,Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, PenileCancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumor, PlasmaCell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma, Pregnancy andBreast Cancer, Primary Central Nervous System (CNS) Lymphoma, ProstateCancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis andUreter, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma,Salivary Gland Cancer, Ewing Sarcoma, Kaposi Sarcoma, Osteosarcoma,Rhadomyosarcoma, Soft Tissue Sarcoma, Uterine Sarcoma, Sézary Syndrome,Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft TissueSarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with OccultPrimary, Metastatic, Stomach (Gastric) Cancer, T-Cell Lymphoma,Cutaneous, Testicular Cancer, Throat Cancer, Thymoma and ThymicCarcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvisand Ureter, Trophoblastic Tumor, Gestational, Unknown Primary, Carcinomaof, Ureter and Renal Pelvis, Transitional Cell Cancer, Urethral Cancer,Uterine Cancer, Endometrial, Uterine Sarcoma, Vaginal Cancer, VulvarCancer, Waldenström, Macroglobulinemia, Wilms Tumor and Women's Cancers.

The compounds of the present invention may be useful in the treatment ofdisease, disorder, syndrome or condition selected from the groupconsisting of inflammation, asthma, chronic obstructive pulmonarydisease, pulmonary fibrosis, inflammatory bowel disease, irritable bowelsyndrome, pain, inflammatory pain, chronic pain, acute pain, fever,migraine, headache, low back pain, fibromyalgia, myofascial disorders,viral infections, influenza, common cold, herpes zoster, hepatitis C,AIDS, bacterial infections, fungal infections, dysmenorrhea, burns,surgical or dental procedures, malignancies hyperprostaglandin Esyndrome, classic Bartter syndrome, synovitis, atherosclerosis, gout,arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis,juvenile onset rheumatoid arthritis, rheumatic fever, ankylosingspondylitis, Hodgkin's disease, systemic lupus erythematosus,vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis,scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis,stroke, diabetes mellitus, cancer, neurodegenerative disorders such asAlzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosisand multiple sclerosis, autoimmune diseases, allergic disorders,rhinitis, ulcers, mild to moderately active ulcerative colitis, familialadenomatous polyposis, coronary heart disease, and sarcoidosis.

The compounds of the present invention may be useful in the treatment ofpain, chronic pain, acute pain, rheumatoid arthritic pain orosteoarthritic pain.

The compounds of the present invention may be useful in the treatment ofinflammation, neurodegenerative disorders such as Parkinson's disease,Alzheimer's disease and amyotrophic lateral sclerosis.

The compounds of the present invention may be useful in the treatmentprevention or management of the cancer.

Compounds of the present invention are indicated both in the therapeuticand/or prophylactic treatment of the above-mentioned conditions. For theabove-mentioned therapeutic uses the dosage administered will, ofcourse, vary with the compound employed, the mode of administration, thetreatment desired and the disorder indicated. The daily dosage of thecompound of the invention may be in the range from 0.05 mg/kg to 100mg/kg.

General Methods of Preparation

The compounds described herein, including compounds of general formula(I), (II), (III), and (IV) and specific examples can be prepared usingtechniques known to one skilled in the art through the reactionsequences depicted in Synthetic Scheme-I, Synthetic Scheme-II, SyntheticScheme-III, Synthetic Scheme-IV, Synthetic Scheme-V, SyntheticScheme-VI, Synthetic Scheme-VII, Synthetic Scheme-VIII, SyntheticScheme-IX, Synthetic Scheme-X and Synthetic Scheme-XI as well as byother methods. Furthermore, in the following schemes, where specificacids, bases, reagents, coupling agents, solvents, etc. are mentioned,it is understood that other suitable acids, bases, reagents, couplingagents etc. may be used and are included within the scope of the presentinvention. Modifications to reaction conditions, for example,temperature, duration of the reaction or combinations thereof, areenvisioned as part of the present invention. The compounds obtained byusing the general reaction sequences may be of insufficient purity.These compounds can be purified by using any of the methods forpurification of organic compounds known to persons skilled in the art,for example, crystallization or silica gel or alumina columnchromatography using different solvents in suitable ratios. All possiblegeometrical isomers and stereo isomers are envisioned within the scopeof this invention.

A general approach for the preparation of a compound of formula (I) or(Ia) is depicted in the Synthetic Scheme-I (wherein ring A, ring B, R¹,R², R³, L, P, Q, W, m, n, and t are as defined with respect to acompound of formula (I)).

An Isocynate compound of formula (Intermediate-IA) may be obtained froma corresponding acid, amide or acid halide derivative.

A compound of formula (Intermediate-IA) can be treated (or coupled) witha compound of formula (Intermediate-IB) to form a compound of formula(Intermediate-IC). The compound of formula (Intermediate-IA) can bereacted with the compound of formula (Intermediate-IB) in solvent suchas DCM, toluene or EDC. According to the process, the compound offormula Intermediate-IC may be isolated or not isolated.

A compound of formula (Intermediate-IC) can be deprotected (e.g.,treated with an acid) to obtain a compound of formula (Ia). The acidused in the conversion of the compound of formula (Intermediate-IC) maybe organic acid such as TFA, CSA or methane sulphonic acid.

A compound of formula (I) (wherein R³ is not hydrogen) can be preparedfrom a compound of formula (Ia) by general alkylation methods by usingC₁₋₈alkyl halide/C₃₋₁₂cycloalkyl halide/C₆₋₁₄aryl halide in the presenceof one or more inorganic bases such as NaH, K₂CO₃ or CsCO₃.

In another approach, the compound of formula (II) can be preparedfollowing the synthetic steps depicted in Synthetic Scheme-II (whereinR¹, R², L, P, Q, W, X¹, X², X³, X⁴, m, n, s and t are as defined withrespect to a compound of formula (II)).

An Isocyanate compound of formula (Intermediate-IIA) may be obtainedfrom a corresponding acid, amide or acid halide derivative. A compoundof formula (Intermediate-IIA) can be treated with (or coupled to) acompound of formula (Intermediate-IIB) to form a compound of formula(Intermediate-IIC). A compound of formula (Intermediate-IIC) can betreated with an acid such as an organic acid (e.g. TFA, CSA or methanesulphonic acid) at room temperature to obtain a compound of formula(II). According to the process, the compound of formula(Intermediate-IIA) can be reacted with the compound of formula(Intermediate-IIB) in a solvent such as DCM, toluene or EDC. Accordingto the process, the compound of formula Intermediate-TIC may be isolatedor not isolated.

An approach for the preparation of compound of formula (IVa) isschematically represented in Synthetic Scheme-III (wherein R¹, R², W, m,and n are as defined with respect to a compound of formula (IV)).

A compound of formula (1) (Scheme-IIIA) can be converted to a compoundof formula (2) by using general oxidation methods known in the art usingoxidizing agents such as KMnO₄, CrO₃, K₂Cr₂O₇ etc. A compound of formula(2) can be converted to a compound of formula (3) by using reactionconditions such as oxalyl chloride/NH₃, thionyl chloride/NH₃ orEDCI/NH₄Cl. A compound of formula (3) can be treated with oxalylchloride in solvents such as EDC or toluene to obtain Intermediate-I(Scheme-IIIA).

A compound of formula (5) (Scheme-IIIB) can be prepared from a compoundof formula (4) according to known procedures in the literature and canbe further converted to a compound of formula (6) by known reducingagents such as Fe/HCl or Zn/HCl. A compound of formula (6) can beconverted to a compound of formula (7) by reacting it with aromatic oraliphatic carbonyl chloride using solvent such as dry THF. A compound offormula (7) can be converted to a compound of formula (8) by hydrolysis,for example with NaOH, KOH or LiOH. A compound of formula (8) can betreated with NaN₃ and conc. H₂SO₄ (e.g., at about 50° C.) to give acompound of formula (9). A compound of formula (9) can be converted to acompound of formula (10) by reaction with an aqueous solution of sodiumnitrite and a solution of stannous chloride in conc. HCl. A compound offormula (10) can be converted to a compound of formula (11) by using anaqueous solution of inorganic bases such as Na₂CO₃ or K₂CO₃ and BOCanhydride in a solvent such as THF or DMF. A compound of formula (11)can be treated with Intermediate-I to obtain a compound of formula (12).The compound of formula (11) can be reacted with the Intermediate-I inan aprotic solvent such as DCM, toluene or EDC to obtain the compound offormula (12). A compound of formula (12) can be treated with organicacid to obtain compound of formula (IVa) (Scheme-IIIB) The organic acidused in the conversion of the compound of formula (12) may be TFA, CSAor methane sulphonic acid.

An approach for the preparation of compound of formula (IIIa) isschematically represented in Synthetic Scheme-IV (wherein R¹, R², Q, m,and n are as defined with respect to a compound of formula (III)).

A compound of formula (13) can be converted to a compound of formula(14) by reaction with an aqueous solution of sodium nitrite and asolution of stannous chloride in conc. HCl, which can be furtherconverted to Intermediate-II by using BOC protection methods known inthe art of synthesis in the presence of inorganic bases such as Na₂CO₃,K₂CO₃ by using aprotic solvents such as THF, DMF at 0-100° C. A compoundof formula (19) can be prepared from a compound of formula (15) byfollowing the reaction steps as given in scheme IIB for a compound offormula (8). Also, a compound of formula (19) can be directly preparedfrom a compound of formula (20) by using2,2,2-trifluoro-N-(hydroxymethyl)acetamide and sulphuric acid. Acompound of formula (19) can be converted to a compound of formula (21)by using reaction conditions such as oxalyl chloride/NH₃, thionylchloride/NH₃ or EDCI/NH₄Cl, which can be further treated with oxalylchloride in a solvent such as EDC or toluene to give a compound offormula (22).

A compound of formula (22) can be treated with Intermediate-II to obtaina compound of formula (23). The compound of formula (22) can be treatedwith the Intermediate-II in an aprotic solvent, such as DCM, toluene orEDC to obtain a compound of formula (23). A compound of formula (23) canbe treated with organic acid to obtain compound of formula (IIIa). Theorganic acid used in the conversion of a compound of formula (23) may beTFA, CSA or methane sulphonic acid. The compound of formula (IIIa) canbe converted to a free amine for further amide derivatization byprocedures known in the art of synthesis.

An approach for the preparation of compound of formula (IIb) isschematically represented in Synthetic Scheme-V (wherein L, W, R¹, R²,R, t, m, and n are as defined with respect to a compound of formula(II)).

A compound of formula (24) can be converted to a compound of formula(25) by using reaction conditions such as oxalyl chloride/NH₃, thionylchloride/NH₃ or EDCI/NH₄Cl, which can be further treated with oxalylchloride in a solvent such as EDC or toluene to give a compound offormula (26). A compound of formula (26) can be treated withIntermediate-III in an aprotic solvent, such as DCM, toluene or EDC toobtain a compound of formula (27), which then further treated with anorganic acid, such as TFA, CSA or methane sulphonic acid at roomtemperature give a compound of formula (28). A compound of formula (28)can be converted to a compound of formula (29) by reduction methodsknown in the art of synthesis such as Pd/C, Fe—HCl or Raney Nickel in asolvent such as MeOH or EtOH, which can be further converted to acompound of formula (30) by iodination using KI followed bydiazotization using PTSA and NaNO₂. A compound of formula (30) can beconverted to a compound of formula (IIb) by a sequence oftransformations such as transition metal catalyzed reactions for exampleSonogashira coupling.

An approach for the preparation of compound of formula (IIc) isschematically represented in Synthetic Scheme-VI (wherein L, W, R¹, R²,R, m, and n are as defined with respect to a compound of formula (II)).

A compound of formula (31) can be converted to a compound of formula(32) by using standard conditions such as oxalyl chloride/NH₃, thionylchloride/NH₃ or EDCI/NH₄Cl, which can be further treated with oxalylchloride in a solvent, such as EDC or toluene to give a compound offormula (33). A compound of formula (33) can be treated with (or coupledto) Intermediate-III in an aprotic solvent, such as DCM, toluene or EDCto obtain a compound of formula (34), which when further treated withorganic acid, such as TFA, CSA or methane sulphonic acid at roomtemperature give a compound of formula (35). A compound of formula (IIc)can be prepared from a compound of formula (35) by using trimethylaluminum and solvents such as toluene, xylene or EDC at a temperature of0-100° C.

Alternatively, the methyl ester of a compound of formula (35) can beconverted to its acid derivative under hydrolysis condition, which canbe further treated with the amines of the formula R—NH₂ to give compoundof formula (IIc) using standard coupling conditions such as EDCI, HBTU,TBTU, DCC etc.

An approach for the preparation of a compound of formula (IVd) isschematically represented in Synthetic Scheme-VII (wherein R¹, R², R, W,m, and n are as defined with respect to a compound of formula (IV)).

A compound of formula (36) can be converted to Intermediate-IV byfollowing the same reaction steps as for Intermediate-I described inscheme IIIA. A compound of formula (11) can be treated withIntermediate-IV in an aprotic solvent, such as DCM, toluene or EDC toobtain a compound of formula (39), which when further treated withorganic acid, such as TFA, CSA or methane sulphonic acid at roomtemperature give a compound of formula (40). A compound of formula (40)can be converted to a compound of formula (IVd) by a sequence oftransformations such as transition metal catalyzed reactions for exampleSonogashira coupling.

In another approach, the compound of formula (IIIb) can be preparedfollowing the synthetic steps depicted in Synthetic Scheme-VIII (whereinX¹, X², X³, R¹, R², Q, m and n are as defined with respect to a compoundof formula (III)).

A compound of formula (41) can be reacted with Q-C(O)LG (wherein LGrepresents a suitable leaving group (e.g., OH or Cl or Br or O-alkyl))under suitable reaction conditions to obtain a compound of formula(IIIb). When LG represents Cl the reaction can be performed in asuitable solvent such as DMF, DCM or THF in the temperature range of0-120° C., optionally in the presence of a suitable base such as DIPEAor Et₃N. Furthermore, when LG represents O-alkyl the reaction can beperformed with a suitable reagent such as trimethylaluminium or a strongbase such as sodium hydride (NaH) in a suitable solvent such as tolueneor DMF. When LG represents OH, the reaction can be performed with asuitable coupling reagent known in the art, for example,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) in a suitablesolvent such as DMF or tetrahydrofuran (THF) in the temperature range of0-120° C., optionally in the presence of a suitable base such as DIPEA(diisopropylethyl amine) or Et₃N. Alternatively, the reaction can beperformed using a suitable reagent such as isobutyl chloroformate,oxalyl chloride or thionyl chloride in a suitable solvent such as DMF,DCM or THF, in the presence of a suitable base such as DIPEA or Et₃N.

In another approach, the compound of formula (III) can be preparedfollowing the synthetic steps depicted in Synthetic Scheme IX (whereinR¹, R², P, Q, X¹, X², X³, m and n are as defined with respect to acompound of formula (III)).

An Isocyanate compound of formula (Intermediate-IIIA) may be obtainedfrom a corresponding acid, amide or acid halide derivative. A compoundof formula (Intermediate-IIIA) can be reacted with a compound of formula(Intermediate-IIIB) to form a compound of formula (Intermediate-IIIC)and the compound of formula (Intermediate-IIIC) can be converted to acompound of formula (III). According to the process, the compound offormula (Intermediate-IIIA) can be reacted with the compound of formula(Intermediate-IIIB) in a solvent such as DCM, toluene or EDC. Accordingto the process, the compound of formula (Intermediate-IIIC) may beisolated or not isolated. According to the process, the compound offormula (Intermediate-IIIC) is converted to compound of formula (III)using an acid. The acid used in the process can be an organic acid suchas TFA, CSA or methane sulphonic acid.

In another approach, the compound of formula (IV) can be preparedfollowing the synthetic steps depicted in Synthetic Scheme-X (whereinR¹, R², L, W, m and n are as defined with respect to a compound offormula (IV)).

An Isocyanate compound of formula (Intermediate-IVA) may be obtainedfrom a corresponding acid, amide or acid halide derivative. A compoundof formula (Intermediate-IVA) can be reacted with a compound of formula(Intermediate-IVB) to form a compound of formula (Intermediate-IVC) andthe compound of formula (Intermediate-IVC) can be converted to acompound of formula (IV). According to the process, the compound offormula (Intermediate-IVA) can be reacted with the compound of formula(Intermediate-IVB) in solvent such as DCM, toluene or EDC. According tothe process, the compound of formula (Intermediate-IVC) may be isolatedor not isolated. According to the process, the compound of formula(Intermediate-IVC) is converted to a compound of formula (IV) using anacid. The acid used in the process can be an organic acid such as TFA,CSA or methane sulphonic acid.

In another approach, the compound of formula (II) can be preparedfollowing the synthetic steps depicted in Synthetic Scheme-XI (whereinR¹, R², L, P, Q, W, X¹, X², X³, X⁴, m, n, s and t are as defined withrespect to a compound of formula (II) and PG¹ represents an amineprotecting group such as, but not limited to, tert-Butoxycarbonyl (Boc)or carboxybenzyl (Cbz) or benzyl.

An Isocyanate compound of formula (Intermediate-IIA*) may be obtainedfrom a corresponding acid, amide or acid halide derivative. A compoundof formula (Intermediate-IIA*) can be reacted with a compound of formula(Intermediate-IIB*) to form a compound of formula (Intermediate-IIC*)and the compound of formula (Intermediate-IIC*) can be converted to thecompound of formula (II). According to the process, the compound offormula (Intermediate-IIA*) can be reacted with the compound of formula(Intermediate-IIB*) in a solvent such as DCM, toluene or EDC. Accordingto the process, the compound of formula Intermediate-IIC* may beisolated or not isolated. According to the process, the compound offormula (Intermediate-IIC*) is converted to compound of formula (II)using an acid. The acid used in the process can be an organic acid suchas TFA, CSA or methane sulphonic acid.

Q, W or other substituents (e.g. R¹ or R²) if present in the formula(I), (II), (III) or (IV) may be transformed into another chemical groupat a chemically compatible stage of the synthetic sequence, in thepresence of a suitable reagent by following the procedures known in theart of organic synthesis to obtain the final compound of formula (I),(II), (III) or (IV).

EXPERIMENTAL

Unless otherwise stated, work-up includes distribution of the reactionmixture between the organic and aqueous phase indicated withinparentheses, separation of layers and drying the organic layer oversodium sulphate (Na₂SO₄), filtration and evaporation of the solventunder reduced pressure. Purification, unless otherwise mentioned,includes purification by silica gel chromatographic techniques, insuitable solvents of a suitable polarity as the mobile phase.Abbreviations used in the description of the chemistry and in theexamples that follow are: AIBN: Azobisisobutyronitrile; NBS:N-Bromosuccinimide; CCl₄: Carbon tetrachloride; CSA: Camphor sulphonicacid; TFA: Trifluoro acetic acid; NaHCO₃: Sodium bicarbonate; PCl₅:Phosphorous pentachloride; POCl₃: Phosphorous oxychloride;NaO^(t)Bu:Sodium O-tert butyl; K₂CO₃:Potassium carbonate; DIPEA:N,N-Diisopropylethylamine; LDA: Lithium diisopropylamide; TEA:Triethylamine; TBAF: Tetra-n-butylammonium fluoride; DCC:N,N′-Dicyclohexylcarbodiimide; HOBT: 1-Hydroxybenzotriazole; TBTU:O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate;HBTU: O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; EDCI:1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; BOP:(Benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate; Boc/BOC: tert-Butoxycarbonyl; BOC anhydride:Di-tert-butyl dicarbonate; Cbz:Benzyloxycarbonyl; DAST:Diethylaminosulfur trifluoride; PTSA: p-Toluenesulfonic acid; DBU:1,8-Diazabicyclo[5.4.0]undec-7-ene; DCM or MDC: Dichloromethane; DEE:Diethylether; DMSO: Di-methyl sulfoxide; THF: Tetrahydrofuran; EDC:Ethylene dichloride; EtOAc or EA: Ethyl acetate; CHCl₃: Chloroform;MeOH: Methanol; RT: Room temperature; h: hours.

Intermediate-12-(4-Bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Step-1:—Preparation of(2E)-1-(4-bromophenyl)-2-(2-chloro-6-fluorobenzylidene) hydrazine

To a solution of 2-chloro-6-fluorobenzaldehyde (1.0 g, 6.32 mmol) inethanol was added (4-bromophenyl)hydrazine (1.7 g, 7.59 mmol) and aq.solution of NaHCO₃ (0.637 g, 4.59 mmol). The reaction mixture wasstirred at RT for 5-6 h. The reaction mass was quenched in water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulphate and concentrated. The obtained crude product waspurified by column chromatography on silica gel, eluting with 4.6% EA:pet. ether to afford 0.650 g of the desired product. ¹H NMR (300 MHz,DMSO d₆): δ 6.98 (d, J=7.8 Hz, 2H), 7.23-7.40 (m, 5H), 8.07 (s, 1H),10.87 (br s, 1H). MS (m/z): 329.17 (M+H)⁺.

Step-2:—Preparation ofN-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbohydrazonoyl chloride

To a solution of(2E)-1-(4-bromophenyl)-2-(2-chloro-6-fluorobenzylidene)hydrazine (0.300g, 1.32 mmol) in benzene (10 mL) was added PCl₅ (0.330 g, 1.58 mmol).The reaction mixture was stirred at RT for 18 h. The reaction mass wasquenched in water, neutralized with NaHCO₃ and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulphate andconcentrated to afford 0.110 g of the desired product. ¹H NMR (300 MHz,DMSO d₆): δ 7.17 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 3H), 7.45-7.61(m, 2H), 10.26 (s, 1H). MS (m/z): 361.34 (M−H)⁻.

Step-3:—Preparation ofN′-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbohydrazonamide

To a cold solution ofN-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbohydrazonoyl chloride(0.070 g, 0.267 mmol) in dry THF was added aq. ammonia. The reactionmass was stirred at 0-5° C. for 2-3 h. The reaction mass was quenched inwater, neutralized with dilute acetic acid and extracted with DCM. Theorganic layer was dried over anhydrous sodium sulphate and concentratedto afford 0.040 g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ6.29 (br s, 2H), 6.80 (d, J=8.4 Hz, 2H), 7.24 (d, J=9.3 Hz, 2H),7.28-7.50 (m, 3H), 8.33 (s, 1H).

Step-4:—Preparation of2-(4-bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

To a cold solution ofN′-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbohydrazonamide (0.050 g,0.146 mmol) in CHCl₃ was added pyridine (0.5 mL) and phosgene (1.0 mL)at 0-5° C. The reaction mass was stirred at 0-5° C. for 2-3 h. Thereaction mass was quenched in water, neutralized with dilute acetic acidand extracted with DCM. The organic layer was dried over anhydroussodium sulphate and concentrated. The obtained crude product waspurified with column chromatography on silica gel eluting with 1.0%MeOH:DCM to afford 0.020 g of the desired product. ¹H NMR (300 MHz, DMSOd₆): δ 7.50 (t, J=8.7 Hz, 1H), 7.56-7.71 (m, 4H), 7.89 (d, J=9.3 Hz,2H), 12.69 (s, 1H). MS (m/z): 368.15 (M)⁺.

Intermediate-25-(2-Chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Step-1:—Preparation of(1E)-1-(2-chloro-6-fluorobenzylidene)-2-(4-iodophenyl)hydrazine

To a solution of (4-iodophenyl)hydrazine (1.0 g, 4.27 mmol) in ethanol(10 mL) was slowly added solution of 2-chloro-6-fluorobenzaldehyde(0.675 g, 4.27 mmol) in ethanol (10 mL). The reaction mass was stirredat RT for 5-6 h. The reaction mass was quenched in water and extractedwith ethyl acetate. The organic layer was concentrated to afford 1.2 gof desired product. ¹H NMR (300 MHz, DMSO d₆): δ 6.87 (d, J=8.4 Hz, 2H),7.26-7.36 (m, 3H), 7.53 (d, J=9.0 Hz, 2H), 8.06 (s, 1H), 10.84 (s, 1H).MS (m/z): 374.87 (M)⁺.

Step-2:—Preparation of2-chloro-6-fluoro-N-(4-iodophenyl)benzenecarbohydrazonoyl chloride

The title compound was prepared according to the procedure described instep-2 of Intermediate-1 using(1E)-1-(2-chloro-6-fluorobenzylidene)-2-(4-iodophenyl)hydrazine (1.2 g,3.20 mmol), PCl₅ (0.990 g, 4.8 mmol) and benzene (20 mL) to afford 1.0 gof desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.00 (d, J=8.7 Hz, 2H),7.41 (d, J=8.7 Hz, 1H), 7.48-7.60 (m, 4H), 10.22 (s, 1H).

Step-3:—Preparation of2-chloro-6-fluoro-N′-(4-iodophenyl)benzenecarbohydrazonamide

The title compound was prepared according to the procedure described instep-3 of Intermediate-1 by using2-chloro-6-fluoro-N-(4-iodophenyl)benzenecarbohydrazonoyl chloride (1.00g, 2.44 mmol), aq. ammonia (2.0 mL) and dry THF (10 mL) to afford 0.900g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 6.28 (br s, 2H),6.70 (d, J=8.4 Hz, 2H), 7.27 (t, J=8.7 Hz, 1H), 7.36-7.42 (m, 3H),7.45-7.51 (m, 1H), 8.33 (s, 1H).

Step-4:—Preparation of5-(2-chloro-6-fluorophenyl)-2-(4-iodophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

The title a compound was prepared according to the procedure describedin step-4 of Intermediate-1 using2-chloro-6-fluoro-N′-(4-iodophenyl)benzene carbohydrazonamide (0.900 g,2.31 mmol), pyridine (0.65 mL, 5.79 mmol), phosgene (2.50 mL, 4.63 mmol)and CHCl₃ (20 mL). The obtained crude product was purified with columnchromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.400g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.47 (t, J=9.0Hz, 2H), 7.54-7.82 (m, 5H), 12.62 (s, 1H). MS (m/z): 414.25 (M−H)⁻.

Step-5:—Preparation of5-(2-chloro-6-fluorophenyl)-2-{4-[(trimethylsilyl)ethynyl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

To a solution of5-(2-chloro-6-fluorophenyl)-2-(4-iodophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(0.200 g, 0.483 mmol) in DMSO (2 mL) was added ethynyl(trimethyl)silane(0.071 g, 0.724 mmol), copper iodide (0.005 g, 0.007 mmol),bis(triphenylphosphine) palladium(II) chloride (0.200 g, mmol) and TEA(2.0 mL). The reaction mass was stirred at RT for 24 h. The reactionmass was quenched in water and neutralized with dilute acetic acid andextracted with DCM. The organic layer was dried over anhydrous sodiumsulphate and concentrated to afford 0.200 g of the desired product. ¹HNMR (300 MHz, DMSO d₆): δ 2.31 (s, 9H), 7.44-7.47 (m, 3H), 7.54-7.71 (m,3H), 7.94-8.01 (m, 1H), 77.95 (br s, 1H). MS (m/z): 384.29 (M−H)⁻.

Step-6:—Preparation of5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

To a solution of5-(2-chloro-6-fluorophenyl)-2-{4-[(trimethylsilyl)ethynyl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(0.200 g, 0.570 mmol) in DCM was added TBAF (0.362 g, 1.11 mmol). Thereaction mass was stirred at RT for 2-3 h. The reaction mass wasquenched in water and filtered through celite bed and concentrated. Theobtained crude product was purified with column chromatography on silicagel eluting with 2.0% MeOH:DCM to afford 0.400 g of the desired product.¹H NMR (300 MHz, DMSO d₆): δ 4.21 (s, 1H), 7.50 (t, J=9.3 Hz, 1H), 7.58(d, J=8.4 Hz, 3H), 7.67-7.71 (m, 1H), 7.96 (d, J=8.1 Hz, 2H), 12.69 (brs, 1H).

Intermediate-31-(4-bromophenyl)-5-chloro-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazole

To2-(4-bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate-1, 0.100 g, 0.271 mmol) was added POCl₃. The reaction masswas refluxed for 48 h. The reaction mass was quenched in water, basifiedwith NaHCO₃ and extracted with ethyl acetate and concentrated. Theobtained crude product was purified with column chromatography on silicagel eluting with 0.5% EA:DCM to afford 0.110 g of the desired product.¹H NMR (300 MHz, DMSO d₆): δ 7.44 (t, J=9.3 Hz, 1H), 7.53 (d, J=7.8 Hz,1H), 7.60-7.68 (m, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.85 (d, J=8.7 Hz, 2H).MS (m/z): 388.22 (M+H)⁺.

Intermediate-4 3-Chloro-4-iodopyridine

To a cold solution of 3-chloro pyridine (1.0 g, 8.88 mmol) in THF (30.0mL) was added LDA (5.9 mL, 8.88 mmol) at −75° C. The reaction mixturewas stirred at −75° C. for 4 h. Iodine (2.2 g, 8.88 mmol) was added andcontinued stirring at −75° C. for 1 h. The reaction mixture was quenchedin water at −70° C., extracted with ethyl acetate and concentrated toafford 0.500 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 8.01 (d,J=5.1 Hz, 1H), 8.14 (d, J=4.8 Hz, 1H), 8.63 (s, 1H).

Intermediate-5 4-(5-Iodopyrimidin-2-yl)morpholine

Step-1:—Preparation of 5-iodopyrimidin-2-amine

To a solution of pyrimidin-2-amine (1.0 g, 0.010 mol) in DMSO (10 mL)was added iodine (3.2 g, 0.012 mol). The reaction mixture was stirred at120° C. for 1 h. The reaction mass was quenched in water and excess ofiodine was neutralised with sodium metabisulphate. The reaction mass wasextracted with ethyl acetate and concentrated to afford 0.400 g of thedesired product.

Step-2:—Preparation of 2-chloro-5-iodopyrimidine

To a solution of 5-iodopyrimidin-2-amine (10.0 g, 0.045 mol) inacetonitrile (150 mL) was added CuCl₂ (11.57 g, 0.067 mol) andtert-butyl nitrite (6.99 g, 0.067 mol). The reaction mass was heated at70° C. for 5-6 h. The reaction mass was diluted with ether and the solidobtained was filtered off. The obtained product was purified with columnchromatography on silica gel eluting with DCM to afford 1.700 g of thedesired product.

Step-3:—Preparation of 4-(5-iodopyrimidin-2-yl)morpholine

The mixture of 2-chloro-5-iodopyrimidine (0.200 g, 0.836 mmol) inmorpholine (3.0 mL) was refluxed for 2-3 h. The reaction mass wasquenched in water and the solid obtained was filtered off. The obtainedsolid was dried to afford 0.180 g of the desired product. ¹H NMR (300MHz, DMSO d₆): δ 3.63 (s, 8H), 8.52 (s, 2H); MS (m/z): 292.25 (M+H)⁺.

Intermediate-6 4-(5-Iodopyridin-2-yl)morpholine

A solution of 2-chloro-5-iodo pyridine (0.200 g, 0.836 mmol) inmorpholine (3.0 mL) was refluxed for 12-15 h. The reaction mass wasquenched in ice and the solid obtained was filtered off to afford 0.170g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.40 (t, J=4.8Hz, 4H), 3.67 (t, J=4.5 Hz, 4H), 6.74 (d, J=8.7 Hz, 1H), 7.77-7.81 (m,1H), 8.28 (s, 1H).

Intermediate-7 tert-Butyl2-[4-(methoxycarbonyl)phenyl]hydrazinecarboxylate

Step-1:—Preparation of methyl 4-aminobenzoate

To a solution of 4-amino benzoic acid (20.0 g, 0.14 mol) in methanol(400 mL) was added conc. sulphuric acid (40 mL). The reaction mass wasstirred at RT for 6-7 h. The reaction mass was quenched with water andbasified with NaHCO₃ and extracted with DCM. The organic layer was driedover anhydrous sodium sulphate and concentrated to afford 15.0 g of thedesired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.72 (s, 3H), 5.96 (br s,2H), 6.55 (d, J=8.1 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H) MS (m/z): 152.21(M+H)⁺.

Step-2:—Preparation of methyl 4-hydrazinylbenzoate

To a cold solution of methyl 4-aminobenzoate (15.0 g, 0.099 mol) inconc. HCl was added aq. solution of sodium nitrite (7.5 g, 0.109 mmol)at 0-5° C. The reaction mass was stirred at RT for 1-2 h. The reactionmass was cooled to 0° C. and stannous chloride (0.049 g, 0.210 mmol) wasadded and further stirred at RT for 2-3 h. The reaction mass wasfiltered to afford 17.0 g of desired product. ¹H NMR (300 MHz, DMSO d₆):δ 3.77 (s, 3H), 7.03 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 10.69(br s, 2H); MS (m/z): 167.28 (M+H)⁺.

Step-3:—Preparation of tert-butyl2-[4-(methoxycarbonyl)phenyl]hydrazinecarboxylate

To a solution of methyl 4-hydrazinylbenzoate (10.0 g, 0.049 mol) in DCM(150 mL) was added TEA (10 mL) and BOC anhydride (10.7 g, 0.049 mmol).The reaction mass was stirred at RT for 12 h. The reaction mass wasquenched in water and extracted with DCM. The organic layer was driedover anhydrous sodium sulphate and concentrated. The obtained solid waswashed with pentane to afford 6.5 g of desired product. ¹H NMR (300 MHz,DMSO d₆): δ 1.40 (s, 9H), 3.74 (s, 3H), 6.65 (d, J=8.4 Hz, 2H), 7.74 (d,J=8.7 Hz, 2H), 8.31 (s, 1H), 8.93 (br s, 1H).

Intermediate-8 2-Chloro-6-fluorobenzoyl isocyanate

Step-1:—Preparation 2-chloro-6-fluorobenzamide

A solution of 2-chloro-6-fluorobenzonitrile (8.0 g, 51.61 mmol) in conc.sulphuric acid (50 mL) was heated at 60-70° C. for 6-7 h. The reactionmass was quenched in water and extracted with DCM. The organic layer wasdried over anhydrous sodium sulphate and concentrated to afford 5.5 g ofdesired product.

Step-2:—Preparation of 2-chloro-6-fluorobenzoyl isocyanate

To a solution of 2-chloro-6-fluorobenzamide (2.0 g, 0.011 mmol) in EDC(10 mL) was added oxalyl chloride (2.18 g, 0.017 mmol). The reactionmass was refluxed for 24 h. Excess of solvent was removed under vacuumto afford 2.0 g of desired product.

Intermediate-94-[3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoicacid

Step-1:—Preparation of tert-butyl2-[(2-chloro-6-fluorobenzoyl)carbamoyl]-2-[4-(methoxycarbonyl)phenyl]hydrazinecarboxylate

To a solution of tert-butyl2-[4-(methoxycarbonyl)phenyl]hydrazinecarboxylate (Intermediate-7, 2.0g, 7.54 mmol) in DCM (15 mL) was added 2-chloro-6-fluorobenzoylisocyanate (Intermediate-8, 1.50 g, 7.54 mmol). The reaction mass wasstirred at RT for 2 h. Excess of solvent was removed under vacuum toafford 3.0 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.42 (s,9H), 3.83 (s, 3H), 7.24-7.46 (m, 5H), 7.94 (d, J=7.2 Hz, 2H), 9.91 (brs, 1H), 11.34-11.39 (br m, 1H); MS (m/z): 464.06 (M−H)⁻.

Step-2:—Preparation of methyl4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate

To a solution of tert-butyl2-[(2-chloro-6-fluorobenzoyl)carbamoyl]-2-[4-(methoxycarbonyl)phenyl]hydrazinecarboxylate(3.0 g, 6.45 mmol) in DCM (30 mL) was added trifluoro acetic acid (2.0mL). The reaction mass was stirred at RT for 2-3 h. Excess of solventwas removed at low temperature. The reaction mass was quenched in iceand filtered off to afford 2.0 g of desired product. ¹H NMR (300 MHz,DMSO d₆): δ 3.86 (s, 3H), 7.51-7.60 (m, 2H), 7.70 (br s, 1H), 8.09 (brs, 4H), 12.79 (br s, 1H); MS (m/z): 348.55 (M+H)⁺.

Step-3:—Preparation of4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoicacid

To a solution of methyl4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate(2.0 g, 5.76 mmol) in THF:water (5 mL:10 mL) was added sodium hydroxide(0.691 g, 17.27 mmol). The reaction mass was stirred at RT for 3 h. Thereaction mass was diluted with water and washed the aqueous layer withdiethyl ether and toluene. The aqueous layer was cooled to 15° C. andacidified with dilute HCl. The reaction mass was filtered off to afford1.0 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.50 (t, J=9.0Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.67-7.74 (m, 1H), 8.06 (s, 4H), 12.77(br s, 1H).

Intermediate-10 tert-Butyl2-[4-methoxy-3-(methoxycarbonyl)phenyl]hydrazinecarboxylate

Step-1:—Preparation of 2-methoxy-5-nitrobenzoic acid

To a solution of 2-chloro-5-nitrobenzoic acid (3.0 g, 0.14 mol) inmethanol (500 mL) was added sodium methoxide (28.1 g, 0.520 mol). Thereaction mass was refluxed for 15 h. Excess of solvent was removed undervacuum and the reaction mass was diluted with water and acidified withdilute HCl to obtain solid which was filtered off to afford 25.0 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.96 (s, 3H), 7.36 (d,J=9.3 Hz, 1H), 8.37 (d, J=9.0 Hz, 1H), 8.45 (s, 1H), 13.32 (br s, 1H));MS (m/z): 198.25 (M+H)⁺.

Step-2:—Preparation of methyl 2-methoxy-5-nitrobenzoate

To a solution of 2-methoxy-5-nitrobenzoic acid (25.0 g, 0.12 mol) in DMF(100 mL) was added K₂CO₃ (26.3 g, 0.19 mol). The reaction mass wasstirred at 80° C. for 1 h followed by addition of methyl iodide (12.3mL, 0.19 mol). The reaction mass was further stirred at 80° C. for 5-6h. The reaction mass was filtered and the obtained filtrate wasconcentrated. The residue was further diluted with water and obtainedsolid was filtered off to afford 20.0 g of desired product. ¹H NMR (300MHz, DMSO d₆): δ 3.83 (s, 3H), 3.97 (s, 3H), 7.38 (d, J=9.3 Hz, 1H),8.41 (dd, J=2.4 Hz & 2.4 Hz, 1H), 8.47 (s, 1H); MS (m/z): 212.44 (M+H)⁺.

Step-3:—Preparation of methyl 5-amino-2-methoxybenzoate

A solution of methyl 2-methoxy-5-nitrobenzoate (20.0 g, 0.097 mol) inmethanol (300 mL) and 10% Pd/C (5.0 g) was stirred under hydrogenatmosphere under 70-80 psi pressure in Parr apparatus for 4-5 h. Thereaction mass was filtered and the obtained filtrate was concentrated toafford 15.0 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.67 (s,3H), 3.74 (s, 3H), 4.96 (br s, 2H), 6.75 (dd, J=2.4 Hz, 1H), 6.85 (d,J=8.7 Hz, 1H), 6.92 (s, 1H); MS (m/z): 182.25 (M+H)⁺.

Step-4:—Preparation of methyl 5-hydrazinyl-2-methoxybenzoate

The title compound was prepared according to the procedure described instep-2 of Intermediate-7 by using methyl 5-amino-2-methoxybenzoate (15.0g, 0.082 mol), stannous chloride (37.25 g, 0.16 mmol), sodium nitrite(6.28 g, 0.091 mmol), conc.HCl (400 mL) and water (100 mL) to afford14.0 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.75 (s, 6H),7.09 (m, 1H), 7.20-7.23 (m, 1H), 7.34 (s, 1H), 10.20 (br s, 2H); MS(m/z): 197.27 (M+H)⁺.

Step-5:—Preparation of tert-butyl2-[4-(methoxycarbonyl)phenyl]hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using methyl 5-hydrazinyl-2-methoxybenzoate(10.0 g, 0.051 mol), DCM (150 mL), TEA (10 mL) and BOC anhydride (11.2g, 0.051 mmol) to afford 2.0 g of desired product. ¹H NMR (300 MHz, DMSOd₆): δ 1.43 (s, 9H), 3.71 (s, 3H), 3.79 (s, 3H), 6.81-6.85 (m, 1H),6.97-6.99 (m, 2H), 7.45 (s, 1H), 8.78 (s, 1H); MS (m/z): 295.19 (M−H)⁻.

Intermediate-115-[3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoic acid

Step-1:—Preparation tert-butyl2-[(2-chloro-6-fluorobenzoyl)carbamoyl]-2-[4-methoxy-3-(methoxycarbonyl)phenyl]hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-1 of Intermediate-9 by using 2-chloro-6-fluorobenzoyl isocyanate(Intermediate-8, 2.0 g, 6.75 mmol), tert-butyl2-[4-methoxy-3-(methoxycarbonyl)phenyl]hydrazinecarboxylate(Intermediate-10, 1.61 g, 8.18 mmol) and DCM (30 mL) to afford 3.0 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.40 (s, 9H), 3.81 (s,6H), 7.13-7.83 (m, 6H), 9.6 (br s, 1H), 11.13 (br s, 1H); MS (m/z):494.05 (M−H)⁻.

Step-2:—Preparation of methyl5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoate

The title compound was prepared according to the procedure described instep-2 of Intermediate-9 by using tert-butyl2-[(2-chloro-6-fluorobenzoyl)carbamoyl]-2-[4-methoxy-3-(methoxycarbonyl)phenyl]hydrazinecarboxylate(3.0 g, 6.06 mmol), DCM (30 mL) and trifluoro acetic acid (3.0 mL) toafford 2.0 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.80 (s,3H), 3.84 (s, 3H), 7.28 (d, J=9.3 Hz, 1H), 7.49 (t, J=8.7 Hz, 1H), 7.57(d, J=8.4 Hz, 1H), 7.65-7.73 (m, 1H), 8.06 (d, J=9.0 Hz, 1H), 8.18 (s,1H), 12.62 (s, 1H); MS (m/z): 376.27 (M−H)⁻.

Step-3:—Preparation of5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoicacid

The title compound was prepared according to the procedure described instep-3 of Intermediate-9 by using of methyl5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoate(1.5 g, 3.97 mol) and sodium hydroxide (0.320 g, 7.95 mmol) to afford0.700 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.84 (s, 3H),7.24 (t, J=9.3 Hz, 1H), 7.48 (t, J=8.7 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H),7.65-7.72 (m, 1H), 8.00 (d, J=8.7 Hz, 1H), 8.17 (s, 1H), 12.60 (s, 1H),12.85 (br s, 1H).

Intermediate-12 1-[2-(Trifluoromethyl)phenyl]cyclopropanamine

To a cold solution of 2-(trifluoromethyl)benzonitrile (1.0 g, 0.58 mmol)in diethyl ether (20 mL) was added titanium isopropoxide (2.0 g, 0.70mmol) at −70° C. and ethyl magnesium bromide (4.30 mL, 12.86 mmol). Thereaction mass was stirred at RT for 2-3 h. Followed by addition of borontrifluoride solution (1.5 mL) and continued stirring for 2 h at RT. Thereaction mass was quenched in 1N HCl and basified with NaOH solution.The obtained crude product was further purified by column chromatographyon silica gel eluting with 1% EtOAC: DCM eluent to afford 0.250 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.82-0.84 (s, 2H),0.91-0.93 (br s, 2H), 2.24 (br s, 2H), 7.41 (t, J=6.6 Hz, 1H), 7.58-7.67(m, 3H).

Intermediate-13 1-[4-(Trifluoromethyl)phenyl]cyclopropanamine

The title compound was prepared according to the procedure described inIntermediate-12 by using of 4-(trifluoromethyl)benzonitrile (1.0 g, 0.58mmol), diethyl ether (20 mL), titanium isopropoxide (2.0 g, 0.70 mmol),ethyl magnesium bromide (4.30 mL, 12.86 mmol) and boron trifluoridesolution (1.5 mL) to afford 0.210 g of desired product. ¹HNMR (CDCl₃): δ1.05 (s, 2H), 1.60 (s, 2H), 1.78 (s, 2H), 7.36 (d, J=7.8 Hz, 2H), 7.55(d, J=8.1 Hz, 2H).

Intermediate-14 tert-Butyl2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate

Step-1:—Preparation of methyl 4-hydrazinyl-2-methoxybenzoate

The title compound was prepared according to the procedure described instep-2 of Intermediate-7 by using methyl 4-amino-2-methoxybenzoate (10.0g, 0.055 mol), stannous chloride (31.00 g, 0.138 mmol), sodium nitrite(4.57 g, 0.066 mmol), 6 N HCl (200 mL) and water (100 mL) to afford 14.0g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.73 (s, 3H), 3.80(s, 3H), 6.51 (d, J=8.4 Hz, 1H), 6.69 (s, 1H), 7.68 (d, J=8.4 Hz, 1H),8.75 (br s, 1H), 10.28 (br hump, 2H); MS (m/z): 197.01 (M+H)⁺.

Step-2:—Preparation of tert-butyl2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazine carboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using methyl 4-hydrazinyl-2-methoxybenzoate(5.0 g, 0.025 mol), DCM (70 mL), TEA (5.0 mL) and BOC anhydride (6.11 g,0.028 mmol) to afford 3.50 g of desired product. ¹H NMR (300 MHz, DMSOd₆): δ 1.40 (s, 9H), 3.68 (s, 3H), 3.72 (s, 3H), 6.26 (s, 2H), 7.59 (d,J=8.7 Hz, 1H), 8.26 (s, 1H), 8.94 (s, 1H); MS (m/z): 297.02 (M+H)⁺.

Intermediate-154-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoicacid

Step-1:—Preparation of tert-butyl2-((2-chloro-6-fluorobenzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-1 of Intermediate-9 by using 2-chloro-6-fluorobenzoyl isocyanate(Intermediate-8, 2.0 g, 6.75 mmol), tert-butyl2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate(Intermediate-14, 2.0 g, 10.10 mmol) and DCM (30 mL) to afford 3.0 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.42 (s, 9H), 3.76 (s,6H), 6.99 (d, J=8.1 Hz, 1H), 7.11 (s, 1H), 7.2-7.50 (m, 4H), 9.88 (s,1H), 11.32 (s, 1H); MS (m/z): 493.92 (M−H)⁻.

Step-2:—Preparation of methyl4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate

The title compound was prepared according to the procedure described instep-2 of Intermediate-9 by using tert-butyl2-((2-chloro-6-fluorobenzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate(3.0 g, 6.06 mmol), DCM (30 mL) and trifluoro acetic acid (2.0 mL) toafford 2.0 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.81 (s,3H), 3.85 (s, 3H), 7.34-7.73 (m, 6H), 12.80 (s, 1H); MS (m/z): 376.16(M−H)⁻.

Step-3:—Preparation of4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoicacid

The title compound was prepared according to the procedure described instep-3 of Intermediate-9 by using of methyl4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(1.0 g, 2.65 mol) and sodium hydroxide (0.210 g, 5.30 mmol) to afford0.600 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.84 (s, 3H),7.59 (t, J=7.8 Hz, 2H), 7.67-7.75 (m, 3H), 7.81 (d, J=8.4 Hz, 1H), 12.58(br, 1H), 12.80 (s, 1H); MS (m/z): 362.21 (M−H)⁻.

Intermediate-16 (4-Fluoro-2-(trifluoromethyl)phenyl)methanamine

To a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (2.0 g) inethanol (10.0 mL) was added Raney Ni (catalytic amount). The reactionmixture was subjected for hydrogenation in Parr apparatus under 50 psifor 2-3 h. The reaction mass was filtered through celite and thefiltrate was concentrated to afford 0.400 g of desired product. ¹HNMR(CDCl₃): δ 3.98 (s, 2H), 7.24 (t, J=9.0 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H),7.54 (t, J=7.8 Hz, 1H); MS [M+H]⁺:194.03.

Intermediate-174-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzamide

Step-1:—Preparation of 4-hydrazinylbenzonitrile

To a cold solution of 4-cyanoaniline (6.0 g, 0.050 mol) in conc. HCl wasadded aq. solution of sodium nitrite (3.85 g, 0.055 mmol) at −15° C. Thereaction mass was stirred at 0-10° C. for 15 minutes and filtered off toremove insolubles. The filtrate was added to stannous chloride in conc.HCl (24.0 g, 0.166 mmol). The reaction mass was stirred at −15° C. for30 minutes. The reaction mass was filtered to afford 5.2 g of desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 7.04 (d, 2H), 7.70 (d, 2H), 9.17(br s, 1H), 10.66 (br s, 2H).

Step-2:—Preparation of tert-butyl 2-(4-cyanophenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using 4-hydrazinylbenzonitrile (10.0 g,0.059 mmol), BOC anhydride (14.5 g, 0.065 mmol), TEA and DCM to afford12.0 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.41 (s, 9H),6.70 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 8.48 (br s, 1H), 9.00(br s, 1H); (M+H)⁺. 233.94.

Step-3:—Preparation of tert-butyl2-((2-chloro-6-fluorobenzoyl)carbamoyl)-2-(4-cyanophenyl)hydrazinecarboxylate

To a solution of tert-butyl 2-(4-cyanophenyl)hydrazinecarboxylate (2.5g, 0.01 mmol) in DCM (15 mL) was added 2-chloro-6-fluorobenzoylisocyanate (Intermediate-8, 2.56 g, 0.012 mmol). The reaction mass wasstirred at RT for 2 h. Excess of solvent was removed under vacuum toafford 4.0 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.42 (s,9H), 7.25-7.38 (m, 2H), 7.47-7.60 (m, 3H), 7.82-7.85 (m, 2H), 9.96 (brs, 1H), 11.43 (br s, 1H); MS (m/z): 431.02 (M+H)⁺.

Step-4:—Preparation of4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzonitrile

The title compound was prepared according to the procedure described instep-2 of Intermediate-9 by using tert-butyl2-((2-chloro-6-fluorobenzoyl)carbamoyl)-2-cyanophenyl)hydrazinecarboxylate(4.0 g, 00.009 mol), DCM (30 mL), trifluoro acetic acid (5.0 mL) toafford 2.2 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.50 (t,1H), 7.58 (d, 1H), 7.70 (q, 1H), 7.95 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.4Hz, 2H), 12.80 (br s, 1H); MS (m/z): 331.80 (M+H)⁺.

Step-5:—Preparation of4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzamide

A solution of4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzonitrile(1.0 g, 0.003 mol) in conc. sulphuric acid (10 mL) was heated to 70° C.for 15 h. The reaction mixture was quenched in ice water. The reactionmass was basified till pH ˜6-6.5 with dilute NaOH. The obtained solidwas filtered off, washed with water and suck dried to afford 0.300 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.36 (br s, 1H), 7.84 (t,1H), 7.57 (d, 1H), 7.67 (d, 1H), 7.98 (m, 5H), 12.70 (br s, 1H); MS(m/z): 333.11 (M+H)⁺.

Intermediate-18 4-Fluoro-N′-hydroxybenzimidamide

To a solution of 4-fluorobenzonitrile (0.500 g, 4.13 mmol) in ethanol (3mL) was added hydroxylamine HCl (0.427 g, 6.19 mmol) and potassiumcarbonate (1.14 g, 8.26 mmol). The reaction mass was stirred at RT for15-17 h. Excess of solvent was removed under vacuum. The obtainedresidue was diluted with water, acidified with dilute HCl and extractedwith DCM. The organic layer was separated, dried over anhydrous sodiumsulphate and concentrated to afford 0.450 g of desired product. ¹H NMR(300 MHz, DMSO d₆): δ 5.84 (br s, 2H), 7.17-7.27 (m, 2H), 7.68-7.73 (m,2H), 9.64 (br s, 1H); MS (m/z): 155.13 (M+H)⁺.

Intermediate-19 4-Chloro-N′-hydroxybenzimidamide

To a solution of 4-chloro benzonitrile (1.000 g, 7.26 mmol) in ethanol(20 mL) was added hydroxylamine HCl (0.752 g, 10.90 mmol) and potassiumcarbonate (3.00 g, 21.80 mmol). The reaction mass was refluxed for 10-12h. Excess of solvent was removed under vacuum and the residue wasdiluted with water, acidified with dilute HCl. Precipitate obtained wasfiltered off and sucked dried to afford 0.500 g of desired product. ¹HNMR (300 MHz, DMSO d₆): δ 5.88 (br s, 2H), 7.42 (d, J=8.1 Hz, 2H), 7.68(d, J=8.4 Hz, 2H), 9.70 (br s, 1H); MS (m/z): 171.13 (M+H)⁺.

Intermediate-20 N′-Hydroxy-3,5-dimethoxybenzimidamide

The title compound was prepared according to the procedure described inIntermediate-19 by using 3,5-dimethoxy benzonitrile (1.00 g, 6.13 mmol),hydroxylamine HCl (0.634 g, 9.23 mmol) and potassium carbonate (2.53 g,18.40 mmol), ethanol (20 mL) to afford 0.400 g of desired product. ¹HNMR (300 MHz, DMSO d₆): δ 3.75 (s, 6H), 5.79 (s, 2H), 6.49 (s, 1H), 6.84(s, 2H), 9.62 (br s, 1H); MS (m/z): 197.11 (M+H)⁺.

Intermediate-21 Methyl4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate

Step-1:—Preparation of 2,6-dichlorobenzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using 2,6-dichlorobenzamide (1.00 g, 5.26mmol), oxalyl chloride (0.795 g, 6.31 mmol) and toluene (10 mL) toafford 1.00 g of desired product.

Step-2:—Preparation of tert-butyl2-((2,6-dichlorobenzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-1 of Intermediate-9 by using 2,6-dichlorobenzoyl isocyanate (1.0 g,3.38 mmol), tert-butyl2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate(Intermediate-14, 0.805 g, 3.72 mmol) and DCM (20 mL) to afford 1.5 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.42 (s, 9H), 3.76 (s,6H), 6.99 (d, J=6.0 Hz, 1H), 7.10 (s, 1H), 7.60-7.37 (m, 3H), 7.67 (d,J=7.8 Hz, 1H), 9.86 (br s, 1H), 11.30 (br s, 1H).

Step-3:—Preparation of methyl4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate

The title compound was prepared according to the procedure described instep-2 of Intermediate-9 by using tert-butyl2-((2,6-dichlorobenzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate(1.5 g, 2.2 mmol), DCM (50 mL) and trifluoro acetic acid (5.0 mL) toafford 0.900 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.78 (s,3H), 3.84 (s, 3H), 7.62-7.30 (m, 5H), 7.82 (d, J=8.7 Hz, 1H), 12.76 (brs, 1H); MS (m/z): 393.85 (M+H)⁺.

Intermediate-22 3-Fluoro-N′-hydroxy-5-(trifluoromethyl)benzimidamide

The title compound was prepared according to the procedure described inIntermediate-19 by using 3-fluoro-5-(trifluoromethyl)benzonitrile (2.00g, 10.0 mmol), hydroxylamine.HCl (1.09 g, 15 mmol) and potassiumcarbonate (2.2 g, 15 mmol), ethanol (20 mL) to afford 0.900 g of thedesired product. ¹H NMR (300 MHz, DMSO d₆): δ 6.10 (s, 2H), 7.69 (d,J=7.8 Hz, 1H), 7.79 (d, J=10.2 Hz, 1H), 10.03 (s, 1H); MS (m/z): 223.17(M+H)⁺.

Intermediate-23 1,4-Dichloro-2-ethynylbenzene

The title compound was prepared according to the procedure described instep-5 and step-6 of Intermediate-2 by using 1,4-dichloro-2-iodobenzene(1.0 g, 3.6 mmol), ethynyl(trimethyl)silane (0.541 g, 5.5 mmol), copperiodide (0.027 g, 0.14 mmol), bis(triphenylphosphine) palladium(II)chloride (0.050 g, 0.072 mmol), TBAF (catalytic) and DCM to afford 0.550g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 4.73 (s, 1H), 7.50(d, J=8.7 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.71 (s, 1H).

Intermediate-24 1-Chloro-3-ethynyl-2-fluorobenzene

The title compound was prepared according to the procedure described instep-5 and step-6 of Intermediate-2 by using1-chloro-2-fluoro-3-iodobenzene (1.0 g, 3.9 mmol),ethynyl(trimethyl)silane (0.541 g, 5.5 mmol), copper iodide (0.027 g,0.14 mmol), bis(triphenylphosphine) palladium(II) chloride (0.050 g,0.072 mmol), TBAF (catalytic) and DCM to afford 0.500 g of desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 4.66 (s, 1H), 7.25 (t, J=8.4 Hz,1H), 7.54 (t, J=7.2 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H).

Intermediate-25 2-Chloro-1-ethynyl-4-(trifluoromethyl)benzene

The title compound was prepared according to the procedure described instep-5 and step-6 of Intermediate-2 by using2-chloro-1-iodo-4-(trifluoromethyl)benzene (1.0 g, 3.2 mmol),ethynyl(trimethyl)silane (0.541 g, 5.5 mmol), copper iodide (0.027 g,0.14 mmol), bis(triphenylphosphine) palladium(II) chloride (0.050 g,0.072 mmol), TBAF (catalytic) and DCM to afford 0.525 g of desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 4.88 (s, 1H), 7.73 (d, J=8.4 Hz,1H), 7.83 (d, J=7.8 Hz, 1H), 8.01 (s, 1H).

Intermediate-264-(3-(5-(Aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide

Step 1: Preparation of2-chloro-5-{[(trifluoroacetyl)amino]methyl}benzoic acid

To a solution of 2-chlorobenzoic acid (0.500 g, 3.49 mmol) in conc.H₂SO₄ was added 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (0.547 g,3.49 mmol). The mixture was stirred at RT for 16 h. The reaction mixturewas poured into ice-water and stirred for 2 h. The precipitate obtainedwas collected by filtration, dried and re-crystallized fromtoluene/butan-2-one (7:1) to afford 0.800 g of the title product. ¹H NMR(300 MHz, DMSO d₆): δ 4.42 (d, J=6.0 Hz, 2H), 7.43 (d, J=9.9 Hz, 1H),7.54 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 10.06 (br s, 1H), 13.47 (br s,1H); MS (m/z): 280.18 (M−H)⁻.

Step 2: Preparation of2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzamide

To a cold solution of 2-chloro-5-{[(trifluoroacetyl)amino]methyl}benzoicacid (1.50 g, 5.33 mmol) in THF:DCM (20:10 mL) was added oxalyl chloride(0.6 mL, 6.40 mmol) and DMF (2-3 drop) at 0° C. The reaction mixture wasstirred at RT for 2 h and concentrated. A solution of the concentratedmass in THF (15 mL) was treated with ammonia gas (purged throughreaction mass) at 0° C. and the reaction mixture was stirred at RT for 1h. The reaction mixture was diluted with ethyl acetate. The reactionmixture was washed with water, dilute HCl and brine. The organic layerwas separated, dried, filtered and concentrated to afford 0.800 g of thedesired product. ¹H NMR (300 MHz, DMSO d₆): δ 4.39 (s, 2H), 7.30-7.34(m, 2H), 7.46 (d, J=7.8 Hz, 1H), 7.63 (s, 1H), 7.90 (s, 1H), 10.06 (s,1H).

Step 3: Preparation of2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzamide (0.700 g, 2.5mmol), oxalyl chloride (0.3 mL, 3.0 mmol) and EDC (30 mL) to afford0.700 g of the desired product.

Step 4: Preparation of tert-butyl2-((2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-1 of Intermediate-9 by using2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (0.700g, 2.2 mmol), tert-butyl 2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (Intermediate-14, 0.675 mL, 2.20 mmol) and DCM (30mL) to afford 1.2 g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ1.39 (s, 9H), 3.09 (m, 6H), 4.48 (s, 2H), 6.22-6.26 (m, 2H), 7.13-7.76(m, 4H), 8.94 (s, 1H), 10.08 (s, 1H), 11.02 (s, 1H); MS (m/z): (M)⁺.602.72.

Step 5: Preparation of methyl4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate

The title compound was prepared according to the procedure described instep-2 of Intermediate-9 by using tert-butyl2-((2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate(1.20 g, 1.99 mmol), TFA (2 mL) and DCM (20 mL) to afford 0.280 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.78 (s, 3H), 3.85 (s,3H), 4.46 (d, J=6.0 Hz, 2H), 7.51 (t, J=8.1 Hz, 1H), 7.65-7.68 (m, 3H),7.78-7.84 (m, 2H), 10.09 (m, 1H), 12.70 (br s, 1H); MS (m/z): (M)⁺.484.95.

Step 6: Preparation of4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide

To a solution of methyl4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(0.200 g, 0.413 mmol) in dry toluene (3 mL) was added3-(trifluoromethyl)aniline (0.100 g, 0.619 mmol) followed by addition oftrimethyl aluminium (2M solution in toluene) (2 mL). The reaction masswas refluxed for 3-4 h. The reaction mass was quenched in water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulphate and concentrated to afford 0.170 g of desired product.¹H NMR (300 MHz, DMSO d₆): δ 3.95 (s, 3H), 4.46 (d, J=6.0 Hz, 2H), 7.56(t, J=6.0 Hz, 2H), 7.59-7.85 (m, 6H), 7.96 (d, J=7.8 Hz, 1H), 8.26 (s,1H), 10.09 (s, 1H), 10.37 (s, 1H), 12.65 (s, 1H); MS (m/z): (M)⁺.614.08.

Step 7: Preparation of4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide

To a solution of4-(3-(2-chloro-6-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide(0.150 g, 0.24 mmol) in THF was added aq. KOH (0.028 g, 0.48 mmol). Themixture was stirred at RT for 3-4 h. The reaction mixture was pouredinto water and extracted in DCM. Organic layer was dried andconcentrated to afford 0.080 g of the title product. ¹H NMR (300 MHz,DMSO d₆): δ 3.92-3.96 (m, 5H), 7.43-7.61 (m, 5H), 7.70-7.85 (m, 3H),7.97 (m, 2H), 8.26 (s, 1H), 10.35 (m, 1H).

Intermediate-27 Methyl4-(3-(2-chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate

Step 1: Preparation of 2-chloro-6-methylbenzamide

A solution of 2-chloro-6-methylbenzonitrile (2.0 g) in conc. sulphuricacid (10 mL) was heated at 100° C. for 3-4 h. The reaction mass wasquenched in ice-water and the solid obtained was filtered. Theprecipitate was suck dried to afford 1.5 g of desired product. ¹H NMR(300 MHz, DMSO d₆): δ 2.28 (s, 3H), 7.21-7.27 (m, 3H), 7.65 (s, 1H),7.91 (s, 1H).

Step 2: Preparation of 2-chloro-6-methylbenzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using 2-chloro-6-methylbenzamide (1.0 g, 5.9mmol), oxalyl chloride (0.894 g, 7.1 mmol) and EDC (20 mL) to afford1.00 g of the desired product.

Step 3: Preparation of tert-butyl2-((2-chloro-6-methylbenzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-1 of Intermediate-9 by using 2-chloro-6-methylbenzoyl isocyanate(0.793 g, 4.06 mmol), tert-butyl2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate(Intermediate-14, 1.2 g, 4.06 mmol) and DCM (30 mL) to afford 1.5 g ofthe desired product.

Step 4: Preparation of methyl4-(3-(2-chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate

The title compound was prepared according to the procedure described instep-2 of Intermediate-9 by using tert-butyl2-((2-chloro-6-methylbenzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate(2.0 g), TFA (5 mL) and DCM (30 mL) to afford 0.700 g of the desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 2.31 (s, 3H), 3.78 (s, 3H), 3.84(s, 3H), 7.40 (s, 1H), 7.49 (s, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.75 (s,1H), 7.81 (d, J=8.7 Hz, 1H), 12.54 (s, 1H); MS (m/z): 373.95 (M+H)⁺.

Intermediate-28 3-(Difluoromethyl)-4-fluoroaniline

Step 1: Preparation of 2-(difluoromethyl)-1-fluoro-4-nitrobenzene

A solution of 2-fluoro-5-nitrobenzaldehyde (3.0 g, 17 mmol) in DCM (50mL) was added DAST (3.42 g, 21 mmol) and stirred at RT for 18 h undernitrogen atmosphere. The reaction mass was quenched in ice-water andextracted with DCM. The organic layer was dried and concentrated toafford 2.5 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.31 (s,1H), 7.69 (t, J=8.7 Hz, 1H), 8.46-8.50 (m, 2H).

Step 2: Preparation of 3-(difluoromethyl)-4-fluoroaniline

A solution of 2-(difluoromethyl)-1-fluoro-4-nitrobenzene (1.2 g, 6.2mmol) in methanol (20 mL) was added iron powder (4.8 g, 24.8 mmol)followed by conc. HCl (5 mL) dropwise. The reaction mass was stirred atRT for 1-2 h. The reaction mass was quenched in ice-water, basified withNaHCO₃ and extracted with DCM. The organic layer was dried andconcentrated to afford 0.800 g of desired product. ¹H NMR (300 MHz, DMSOd₆): δ 5.25 (s, 2H), 6.66-6.73 (m, 2H), 6.86-7.04 (m, 2H).

Intermediate-29 3-(Difluoromethyl)aniline

Step 1: Preparation of 1-(difluoromethyl)-3-nitrobenzene

The title compound was prepared according to the procedure described instep-1 of Intermediate-28 by using 3-nitrobenzaldehyde (2.0 g, 13 mmol),DAST (2.55 g, 15 mmol) and DCM (30 mL) to afford 1.5 g of desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 7.21 (s, 1H), 7.83 (t, J=8.1 Hz,1H), 8.05 (m, 1H), 8.40 (br s, 2H).

Step 2: Preparation of 3-(difluoromethyl)aniline

The title compound was prepared according to the procedure described instep-2 of Intermediate-28 by using 1-(difluoromethyl)-3-nitrobenzene(1.0 g, 5.0 mmol), Iron powder (3.0 g, 15.0 mmol), conc. HCl (5 mL) andmethanol (20 mL) to afford 0.700 g of desired product. ¹H NMR (300 MHz,DMSO d₆): δ 5.36 (br s, 2H), 6.62-6.82 (m, 4H), 7.11 (t, J=7.8 Hz, 1H);MS (m/z): 144.05 (M+H)⁺.

Intermediate-30 Methyl4-(3-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate

Step 1: Preparation of methyl4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoatehydrochloride

A solution of methyl4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-5 of Intermediate-26, 0.500 g) in methanol (20 mL) was added conc.HCl (5 mL) dropwise. The reaction mass was refluxed for 24 h. Thereaction mass was concentrated to afford 0.450 g of desired product. ¹HNMR (300 MHz, DMSO d₆): δ 3.78 (s, 3H), 3.85 (s, 3H), 4.10 (d, J=5.4 Hz,2H), 7.63 (d, J=9.0 Hz, 1H), 7.74-7.84 (m, 4H), 7.94 (s, 1H), 8.57 (s,2H), 12.81 (s, 2H); MS (m/z): 388.96 (M+H)⁺.

Step 2: Preparation of methyl4-(3-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate

A solution of methyl4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoatehydrochloride (0.500 g, 1.29 mmol) in THF (20 mL) was added DIPEA (2 mL)and cyclopropyl carbonyl chloride (0.201 g, 1.9 mmol) under nitrogenatmosphere. The reaction mass was stirred at RT for 2-4 h. The reactionmass was quenched in water, extracted with DCM and concentrated toafford 0.400 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.69 (m,4H), 1.60 (s, 1H), 3.79 (s, 3H), 3.86 (s, 3H), 4.33 (d, J=5.4 Hz, 2H),7.41-7.54 (m, 3H), 7.61 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.79 (d, 1H),8.71 (m, H); MS (m/z): 456.97 (M+H)⁺.

Intermediate-31 N¹,4,5-Trimethylbenzene-1,2-diamine

Step 1: Preparation of N¹,4,5-trimethyl-2-nitroaniline

A solution of 4,5-dimethyl-2-nitroaniline (2.00 g, 12 mmol) in toluene(25 mL) was added NaOH (1.93 g, 48 mmol). The reaction mass was stirredat 100° C. for 1 h, followed by addition of dimethyl sulphate (4.6 g, 36mmol) and reaction mass was stirred at RT for 24 h. The reaction masswas quenched in water, extracted with DCM and concentrated to afford 1.5g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 2.11 (s, 3H), 2.24(d, J=7.8 Hz, 3H), 2.92 (s, 3H), 6.77 (m, 1H), 7.79 (m, 1H), 8.06 (s,1H); MS (m/z): 180.92 (M+H)⁺.

Step 2: Preparation of N¹,4,5-trimethylbenzene-1,2-diamine

The title compound was prepared according to the procedure described instep-2 of Intermediate-28 by using N¹,4,5-trimethyl-2-nitroaniline(0.350 g, 1.9 mmol), methanol (20 mL), Iron powder (1.75 g, 9.75 mmol),conc. HCl (5 mL) to afford 0.120 g of desired product.

Intermediate-323-(2-Chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one

Step-1:—Preparation of 4-fluoro-2-methoxy-1-nitrobenzene

To a solution of 4-fluoro-2-hydroxy-1-nitrobenzene (5.0 g, 31.8 mmol) inDMF (10 mL) was added K₂CO₃ (13.1 g, 95.4 mmol). The reaction mixturewas stirred at RT for 1 h followed by addition of methyl iodide (9.93 g,69.9 mmol) and the reaction mixture was stirred at 60° C. for 2 h. Thereaction mass was concentrated and quenched in water. The reaction masswas basified with saturated sodium bicarbonate solution and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulphate and concentrated to afford 4.5 g of desired product. ¹H NMR(300 MHz, DMSO d₆): δ 3.93 (s, 3H), 6.97 (t, J=7.8 Hz, 1H), 7.31 (d,J=8.7 Hz, 1H), 8.02 (s, 1H).

Step-2:—Preparation of (3-methoxy-4-nitrophenyl)hydrazine

To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (2.5 g, 14.60 mmol)in ethanol (25 mL) was added hydrazine hydrate (2.1 g, 43.8 mmol). Thereaction mixture was refluxed for 3-4 h. The reaction mixture wasconcentrated to afford 2.0 g of desired product. ¹H NMR (300 MHz, DMSOd₆): δ 3.84 (s, 3H), 4.46 (s, 2H), 6.31 (d, J=9.3 Hz, 1H), 6.50 (s, 1H),7.83 (d, J=9.3 Hz, 1H), 8.25 (s, 1H); MS (m/z): (184.01 M)⁺.

Step-3:—Preparation of tert-butyl2-(3-methoxy-4-nitrophenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using (3-methoxy-4-nitrophenyl)hydrazine(0.500 g, 2.68 mmol), BOC anhydride (0.703 g, 3.22 mmol), sodiumcarbonate (0.426 g, 4.02 mmol) and DCM to afford 0.200 g of desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 1.36 (s, 9H), 3.81 (s, 3H),6.25-6.29 (m, 2H), 7.87 (d, J=8.7 Hz, 1H), 7.78 (s, 1H), 9.12 (s, 1H);MS (m/z): 283.88 (M)⁺.

Step-4:—Preparation of3-(2-chloro-6-fluorophenyl)-1-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared according to the procedure described instep-1 and step-2 of Intermediate-9 by using tert-butyl2-(3-methoxy-4-nitrophenyl) hydrazinecarboxylate (1.0 g) and2-chloro-6-fluorobenzoyl isocyanate (Intermediate-8, 1.0 g), TFA (5 mL)and DCM (40 mL) to afford 0.900 g of desired product. ¹H NMR (300 MHz,DMSO d₆): δ 3.96 (s, 3H), 7.51 (t, J=8.7 Hz, 1H), 7.59 (d, J=7.8 Hz,1H), 7.68-7.73 (m, 2H), 7.88 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 12.93 (s,1H); MS (m/z): 363 (M)⁻.

Step-5:—Preparation of1-(4-amino-3-methoxyphenyl)-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared according to the procedure described instep-2 of Intermediate-28 by using3-(2-chloro-6-fluorophenyl)-1-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one(0.100 g), iron powder (catalytic), conc.HCl (5-6 drops) and methanol (5mL) to afford 0.070 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ3.77 (s, 3H), 4.81 (s, 2H), 6.66 (d, J=8.7 Hz, 1H), 7.17 (d, J=8.1 Hz,1H), 7.26 (s, 1H), 7.50-7.57 (m, 2H), 7.68 (m, 1H), 12.39 (s, 1H).

Step-6:—Preparation of3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one

To a solution of1-(4-amino-3-methoxyphenyl)-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazol-5(4H)-one(0.280 g, 0.83 mmol) in acetonitrile (5.0 ml) was added PTSA (0.477 g,2.51 mmol). The reaction mass was stirred at RT for 1 h followed byaddition of potassium iodide (0.347 g, 2.0 mmol) and sodium nitrite(0.115 g, 1.67 mmol) at 0-5° C. and further stirred for 2 h. Excesssolvent was removed under vacuum and the residue reaction mass wasquenched in water and extracted with ethyl acetate. The organic layerwas washed with sodium metabisulphate and concentrated to obtain a crudeproduct, which was further purified by column chromatography on silicagel eluting with 10% EtOAc: pet. ether to afford 0.200 g of desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 3.85 (s, 3H), 7.40 (d, J=8.7 Hz,1H), 7.46-7.74 (m, 4H), 7.83 (d, J=8.1 Hz, 1H), 12.71 (br s, 1H); MS(m/z): 445.84 (M+H)⁺.

Intermediate-33 2-Chloro-6-iodobenzoyl isocyanate

Step-1:—Preparation of 2-chloro-6-iodobenzoic acid

To the cold solution of 2-amino-6-chlorobenzoic acid (2.0 g, 11.6 mmol)in conc. HCl (10 mL) was added aq. solution of sodium nitrite (0.8 g,11.6 mmol) at 0° C. followed by addition of solution of potassium iodide(2.88 g, 17.4 mmol) in water and conc. sulphuric acid (1 mL). Thereaction mixture was refluxed for 2 h. The reaction mass was washed withsodium metabisulphate solution and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulphate and concentratedto afford 2.0 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.08(t, J=7.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 8.37(br s, 1H); MS (m/z): 280.59 (M)⁻.

Step-2:—Preparation of 2-chloro-6-iodobenzamide

The title compound was prepared according to the procedure described instep-2 of Intermediate-26 by using 2-chloro-6-iodobenzoic acid (2.7 g,9.6 mmol), oxalyl chloride (1.4 g, 11.5 mmol), ammonia gas, THF (20 mL)and DCM (10 mL) to afford 2.3 g of the desired product. ¹H NMR (300 MHz,DMSO d₆): δ 7.11 (t, J=7.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.73 (s,1H), 7.80 (d, J=7.8 Hz, 1H), 8.00 (s, 1H); MS (m/z): 281.98 (M+H)⁺.

Step-3:—Preparation of 2-chloro-6-iodobenzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using 2-chloro-6-iodobenzamide (1.0 g, 3.5mmol), oxalyl chloride (0.538 g, 4.2 mmol) and EDC (20 mL) to afford1.00 g of the desired product.

Intermediate-344-(3-(2-Chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide

Step-1:—Preparation of methyl4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate

The title compound was prepared according to the procedure described instep-1 and step-2 of Intermediate-9 by using tert-butyl2-(3-methoxy-4-(methoxycarbonyl)phenyl) hydrazinecarboxylate(Intermediate-14, 1.0 g) and 2-chloro-6-iodobenzoyl isocyanate(Intermediate-33, 1.0 g), TFA (5 mL) and DCM (40 mL) to afford 0.900 gof desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.78 (s, 3H), 3.85 (s,3H), 3.37 (t, J=7.8 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.70-7.81 (m, 3H),8.00 (d, J=7.8 Hz, 1H), 12.65 (br s, 1H); MS (m/z): 285.75 (M+H)⁺.

Step-2:—Preparation of4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide

The title compound was prepared by following the procedure as describedfor step-6 of Intermediate-26 by using methyl4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(0.100 g, 0.206 mmol), 3-(trifluoromethyl)aniline (0.041 g, 0.247 mmol),trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (10.0mL) to afford 0.075 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ3.95 (s, 3H), 7.19-8.03 (m, 9H), 8.25 (s, 1H), 10.36 (s, 1H), 12.65 (s,1H); MS (m/z): 614.98 (M+H)⁺.

Intermediate-354-(3-(5-(Aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide

Step-1:—Preparation of4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide

The title compound was prepared by following the procedure as describedfor step-6 of Intermediate-26 by using methyl4-(3-(2-chloro-6-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Step-5 of Intermediate-26, 0.100 g, 0.20 mmol),3-(difluoromethyl)-4-fluoroaniline (0.050 g, 0.30 mmol), trimethylaluminium (2M solution in toluene) (1 mL) to afford 0.070 g of desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 3.95 (s, 3H), 4.47 (s, 2H), 6.71(m, 1H), 7.04 (m, 1H), 7.34-7.40 (m, 1H), 7.50-7.54 (m, 1H), 7.65-7.70(m, 3H), 7.79-7.87 (m, 3H), 8.12 (s, 1H), 10.09 (m, 1H), 10.28 (s, 1H),12.67 (brs, 1H); MS (m/z): 614.04 (M+H)⁺.

Step-2:—Preparation of4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide

The solution of4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide(0.070 g, 0.11 mmol) in 20% aq. KOH (10 mL) and aq. NH₃ (2 mL) wasstirred for 24 h at RT. Excess of solvent was removed under vacuum andfiltered off to afford 0.015 g of desired product.

Intermediate-36 N-(3-Amino-4-chlorobenzyl)cyclopropanecarboxamide

Step-1:—Preparation ofN-(4-chloro-3-nitrobenzyl)-2,2,2-trifluoroacetamide

To a solution of 1-chloro-2-nitrobenzene (10.0 g, 0.063 mmol) in conc.sulphuric acid (150 mL) was added N-hydroxy methyl trifluoro acetamide(9.98 g, 0.069 mmol). The reaction mixture was heated at 70-80° C. for24 h. The reaction mass was quenched in ice cold water, neutralised withsodium hydroxide and extracted with DCM. The organic layer wasconcentrated and the obtained crude product was purified by columnchromatography on silica gel eluting with 4% EtOAc: pet. ether to afford5.5 g of desired product. ¹H NMR (300 MHz, DMSO d₆): 4.48 (d, J=3.9 Hz,2H), 7.62-7.64 (m, 1H), 7.72-7.78 (m, 1H), 7.97-8.01 (m, 1H), 10.09(brs, 1H).

Step-2:—Preparation of (4-chloro-3-nitrophenyl)methanamine hydrochloride

To a solution of N-(4-chloro-3-nitrobenzyl)-2,2,2-trifluoroacetamide(0.800 g) in methanol (20 mL) was added conc. HCl (2.0 ml). The reactionmass was refluxed for 18 h. Excess solvent was removed under vacuum toafford 0.700 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.18 (s,1H), 7.35 (s, 1H), 7.52 (s, 1H), 7.86 (s, 2H), 8.28 (s, 1H), 8.72 (br s,2H).

Step-3:—Preparation of N-(4-chloro-3-nitrobenzyl)cyclopropanecarboxamide

The title compound was prepared by following the procedure as describedin step-2 of Intermediate-30 by using(4-chloro-3-nitrophenyl)methanamine hydrochloride (0.700 g, 3.14 mmol),cyclopropylcarbonyl chloride (0.490 g, 4.71 mmol), DIPEA (3.0 mL) andTHF (15 mL) to afford 0.400 g of desired product. ¹H NMR (300 MHz, DMSOd₆): δ 0.69 (d, J=6.0 Hz, 2H), 1.55-1.61 (m, 1H), 4.33 (d, J=6.0 Hz),7.55 (d, J=7.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 8.68 (brs, 1H); MS (m/z): 255.09 (M+H)⁺.

Step-4:—Preparation of N-(3-amino-4-chlorobenzyl)cyclopropanecarboxamide

The title compound was prepared by following the procedure as describedin step-2 of Intermediate-28 by usingN-(4-chloro-3-nitrobenzyl)cyclopropanecarboxamide (0.400 g), methanol(10 mL), iron powder (catalytic) and conc.HCl (5 mL). The reaction masswas refluxed for 2 h. The reaction mass was quenched in water andbasified with NaHCO₃ and extracted with DCM. The organic layer was driedover anhydrous sodium sulphate and concentrated to afford 0.200 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.65 (d, J=8.4 Hz, 4H),1.57 (m, 1H), 4.11 (d, J=5.4 Hz, 2H), 5.34 (s, 2H), 6.41 (d, J=7.2 Hz,1H), 7.10 (d, J=7.8 Hz, 1H), 8.50 (br s, 1H); MS (m/z): 225.07 (M+H)⁺.

Intermediate-37N-(3-(1-(4-Amino-3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4-chlorobenzyl)cyclopropanecarboxamide

Step-1:—Preparation of tert-butyl2-((2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl)carbamoyl)-2-(3-methoxy-4-nitrophenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-1 of Intermediate-9 by using2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3of Intermediate-26, 1.400 g, 4.57 mmol), tert-butyl2-(3-methoxy-4-nitrophenyl)hydrazinecarboxylate (step-3 ofIntermediate-32, 1.30 g, 4.57 mmol) and DCM 30 mL) to afford 2.0 g ofthe desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.33-1.46 (m, 9H),3.87 (s, 3H), 4.40 (s, 2H), 7.06 (d, J=8.4 Hz, 1H), 7.32-7.36 (m, 3H),7.45-7.52 (m, 1H), 7.96 (d, J=8.7 Hz, 1H), 9.92 (s, 1H), 10.07 (br s,1H), 11.13 (br s, 1H); MS (m/z): 589.69 (M)⁺.

Step-2:—Preparation ofN-(4-chloro-3-(1-(3-methoxy-4-nitrophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described instep-2 of Intermediate-9 by using tert-butyl2-((2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl)carbamoyl)-2-(3-methoxy-4-nitrophenyl)hydrazinecarboxylate(2.0 g, 4.23 mmol), TFA (30 mL) and DCM (5 mL) to afford 1.300 g of thedesired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.96 (s, 3H), 4.47 (d,J=5.4 Hz, 2H), 7.54 (d, J=8.7 Hz, 1H), 7.67-7.74 (m, 3H), 7.93 (s, 1H),8.10 (d, J=9.0 Hz, 1H), 10.11 (m, 1H), 12.86 (br s, 1H); MS (m/z):471.88 (M+H)⁺.

Step-3:—Preparation of3-(5-(aminomethyl)-2-chlorophenyl)-1-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one

The solution ofN-(4-chloro-3-(1-(3-methoxy-4-nitrophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(0.500 g, 1.06 mmol) in 20% aq. KOH (20 mL) was stirred for 2-3 h at RT.Excess of solvent was removed under vacuum and filtered off remainingreaction mass to afford 0.400 g of desired product. ¹H NMR (300 MHz,DMSO d₆): δ1.80 (br s, 2H), 3.72 (s, 2H), 3.91 (s, 3H), 7.27-7.39 (m,2H), 7.78 (d, J=9.9 Hz, 2H), 8.98 (d, J=8.7 Hz, 1H), 8.25 (s, 1H); MS(m/z): 375.91 (M)⁺.

Step-4:—Preparation ofN-(4-chloro-3-(1-(3-methoxy-4-nitrophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanecarboxamide

The title compound was prepared according to the procedure as describedin step-2 Intermediate-30 by using3-(5-(aminomethyl)-2-chlorophenyl)-1-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one(0.500 g, 1.33 mmol), cyclopropylcarbonyl chloride (0.207 g, 1.99 mmol),DIPEA (2.0 mL) and THF (30 mL) to afford 0.300 g of crude product whichwas triturated with methanol:DEE to afford 0.300 g of pure product. ¹HNMR (300 MHz, DMSO d₆): δ 0.69 (s, 4H), 1.60 (m, 1H), 3.97 (s, 3H), 4.33(d, J=5.4 Hz, 2H), 7.42-7.55 (m 3H), 7.70 (d, J=8.4 Hz, 1H), 7.87 (s,1H), 8.12 (d, J=8.7 Hz, 1H), 8.69-8.71 (m, 1H), 12.83 (s, 1H); MS (m/z):442.14 (M−H)⁻.

Step-5:—Preparation ofN-(3-(1-(4-amino-3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4-chlorobenzyl)cyclopropanecarboxamide

The title compound was prepared according to the procedure as describedin step-2 Intermediate-28 by usingN-(4-chloro-3-(1-(3-methoxy-4-nitrophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanecarboxamide(0.500 g, 1.12 mmol), iron powder (catalytic amount), methanol (20 mL),conc. HCl (5.0 mL) to afford 0.350 g of desired product. ¹H NMR (300MHz, DMSO d₆): δ 0.69 (s, 4H), 1.22 (br s, 2H), 1.60 (m, 1H), 3.97 (s,3H), 4.33 (d, J=5.4 Hz, 2H), 7.45-7.58 (m, 3H), 7.70 (d, J=9.3 Hz, 1H),7.87 (s, 1H), 8.13 (d, J=9.0 Hz, 1H), 8.71 (m, 1H), 12.30 (br s, 1H); MS(m/z): 414.09 (M+H)⁺.

Intermediate-384-(3-(2,6-Dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(4-(methylthio)phenyl)benzamide

The title compound was prepared according to the procedure as describedfor step-6 of Intermediate-26 by using methyl4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-21, 0.150 g, 0.380 mmol), 4-(methylthio)aniline (0.079 g,0.570 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and drytoluene (5.0 mL) to afford 0.080 g of desired product. ¹H NMR (300 MHz,DMSO d₆): δ 2.46 (s, 3H), 3.94 (s, 3H), 7.26 (d, J=8.4 Hz, 2H),7.69-7.72 (m, 6H), 7.78 (d, J=6.9 Hz, 1H), 7.82 (s, 1H), 10.06 (s, 1H),12.76 (br s, 1H); MS (m/z): 501.0 (M)⁺.

Intermediate-394-(3-(5-(Aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)phenyl)-2-methoxybenzamide

Step-1:—Preparation of4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)phenyl)-2-methoxybenzamide

The title compound was prepared according to the procedure described instep-6 of Intermediate-26 by using methyl4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-5 of Intermediate-26, 0.100 g, 0.20 mmol),3-(difluoromethyl)aniline (Intermediate-29, 0.045 g, 0.30 mmol),trimethyl aluminium (2M solution in toluene) (1.0 mL) and dry toluene(5.0 mL) to afford 0.080 g of crude product which was triturated withmethanol:DCM:ether to afford 0.080 g of pure product. ¹H NMR (300 MHz,DMSO d₆): δ 3.95 (s, 3H), 4.47 (d, J=5.7 Hz, 2H), 7.05 (m, 1H), 7.30 (m,1H), 7.50 (d, J=7.8 Hz, 2H), 7.70 (m, 3H), 7.80 (d, J=6.3 Hz, 3H), 8.08(s, 1H), 10.11 (br s, 1H), 10.28 (s, 1H), 12.72 (br s, 1H); MS (m/z):596.12 (M+H)⁺.

Step-2:—Preparation of4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)phenyl)-2-methoxybenzamide

The solution of4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)phenyl)-2-methoxybenzamide(0.070 g, 0.11 mmol) in 20% aq. KOH (10 mL) and aq. NH₃ (2 mL) wasstirred for 24 h at RT. Excess of solvent was removed under vacuum andfiltered off to afford 0.015 g of desired product.

Intermediate-40 Methyl4-(3-(2-chloro-5-(N-cyclopropylsulfamoyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate

Step-1:—Preparation of 2-chloro-5-(chlorosulfonyl)benzoic acid

To a solution of 2-chlorobenzoic acid (5.0 g, 31.93 mmol) was slowlyadded chlorosulphonic acid (25 mL). The reaction mixture was heated at100° C. for 5-6 h, followed by stirring at RT for 24 h. The reactionmass was quenched in ice cold water slowly and the solid obtained wasfiltered off, washed with water and dried to afford 4.0 g of pureproduct. ¹H NMR (300 MHz, DMSO d₆): δ 7.50 (d, J=7.8 Hz, 1H), 7.68 (d,J=8.1 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 12.69-12.94 (br s, 1H).

Step-2:—Preparation of 2-chloro-5-(N-cyclopropylsulfamoyl)benzoic acid

To a solution of 2-chloro-5-(chlorosulfonyl)benzoic acid (4.0 g, 15.68mmol) in DCM (60 mL) was added cyclopropyl amine (1.8 g, 31.57 mmol) andthe reaction mixture was stirred at RT for 16 h. The reaction mass wasconcentrated and the residue was diluted with ice cold water andacidified with dilute HCl. The crude solid was filtered off, washed withwater and dried to afford 3.0 g of pure product. ¹H NMR (300 MHz, DMSOd₆): δ 0.37 (s, 2H), 0.49 (d, J=5.4 Hz, 2H), 2.12-2.13 (m, 1H), 7.82 (d,J=8.4 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 8.13 (s, 1H), 8.18 (s, 1H), 13.92(br s, 1H).

Step-3:—Preparation of 2-chloro-5-(N-cyclopropylsulfamoyl)benzamide

The title compound was prepared by following procedure as described forstep-2 of Intermediate-26 by using2-chloro-5-(N-cyclopropylsulfamoyl)benzoic acid (3.0 g, 10.0 mmol), DCM(30 mL), oxalyl chloride, ammonia gas (1.2 mL, 13.0 mmol), DMF (2-3drop) and THF (40 mL) to afford 2.500 g of the desired product. ¹H NMR(300 MHz, DMSO d₆): δ 0.41 (m, 2H), 0.47-0.51 (m, 2H), 2.12 (m, 2H),7.74-7.82 (m, 4H), 8.11 (br s, 2H); MS (m/z): 273.00 (M−H)⁻.

Step-4:—Preparation of 2-chloro-5-(N-cyclopropylsulfamoyl)benzoylisocyanate

To a solution of 2-chloro-5-(N-cyclopropylsulfamoyl)benzamide (1.50 g,5.46 mmol) in EDC (20 mL) was added oxalyl chloride (0.59 mL, 6.55mmol). The reaction mass was refluxed for 1-2 h. Excess of solvent wasremoved under vacuum to afford 1.5 g of desired product.

Step-5:—Preparation of tert-butyl2-((2-chloro-5-(N-cyclopropylsulfamoyl)benzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate

To a solution of tert-butyl2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate(Intermediate 14, 1.5 g, 5.08 mmol) in DCM (20 mL) was added2-chloro-5-(N-cyclopropylsulfamoyl)benzoyl isocyanate (1.6 g, 5.32mmol). The reaction mass was stirred at RT for 2 h. Excess of solventwas removed under vacuum to afford 0.500 g of desired product. ¹H NMR(300 MHz, DMSO d₆): δ 0.50 (m, 4H), 1.41 (s, 9H), 2.11 (m, 1H),3.68-3.75 (m, 6H), 7.59 (d, J=8.7 Hz, 1H), 7.78-7.87 (m, 4H), 8.10 (m,2H), 8.27 (s, 1H), 8.95 (s, 1H).

Step-6:—Preparation of methyl4-(3-(2-chloro-5-(N-cyclopropylsulfamoyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate

The title compound was prepared according to the procedure described instep-2 of Intermediate-9 by using tert-butyl2-((2-chloro-5-(N-cyclopropylsulfamoyl)benzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate(0.500 g, 0.83 mmol), TFA (2 mL) and DCM (10 mL) to afford 0.100 g ofthe desired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.40 (m, 2H), 0.52 (d,J=5.4 Hz, 2H), 2.18 (m, 1H), 3.77 (s, 3H), 3.85 (s, 3H), 7.65 (d, J=9.0Hz, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.93 (s, 2H), 8.18 (s, 2H), 12.8 (br s,1H); MS (m/z): 478.97 (M+H)⁺.

Intermediate-41 Methyl4-(3-(2,6-dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate

To a solution of methyl4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-21, 0.100 g, 0.25 mmol) in dry DMF (3 mL) was added NaH(0.012 g, 0.30 mmol) at 0° C. and the reaction mixture was stirred for20-30 minutes. Ethyl bromide (0.028 g, 0.25 mmol) was added and thereaction mixture was further stirred at 60° C. for 5-6 h. The reactionmass was quenched with water and extracted in ethyl acetate. The organiclayer was dried and concentrated to afford 0.040 g of the crude productwhich was further purified by column chromatography in basic aluminaeluting with 0.5-1.0% methanol:DCM to afford 0.040 g of pure product. ¹HNMR (300 MHz, DMSO d₆): δ 1.13 (t, 3H), 3.54-3.56 (m, 2H), 3.78 (s, 3H),3.86 (s, 3H), 7.65 (d, J=8.4 Hz, 1H), 7.77 (m, 4H), 7.84 (d, J=8.4 Hz,1H); MS (m/z): 421.95 (M+H)⁺.

Intermediate-42 Methyl4-(3-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoate

Step-1:—Preparation of methyl4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoate

The title compound was prepared according to the procedure described instep-1 and step-2 of Intermediate-9 by using2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3of Intermediate-26, 1.300 g, 4.2 mmol) and tert-butyl2-[4-(methoxycarbonyl)phenyl]hydrazinecarboxylate (Intermediate-7, 1.150g, 3.8 mmol) in TFA (5-7 mL) and DCM (40 mL). The reaction mass wasquenched with water and extracted with DCM. The organic layer was driedover anhydrous sodium sulphate and concentrated to afford 1.300 g of thedesired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.84 (s, 3H), 4.44 (d,J=5.7 Hz, 2H), 7.49 (t, 1H), 7.66 (d, J=8.7 Hz, 2H), 8.04-8.13 (m, 4H),10.07 (m, 1H), 12.69 (s, 1H); MS (m/z): 453.14 (M−H)⁻.

Step-2:—Preparation of methyl4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoatehydrochloride

The title compound was prepared according to the procedure described instep-1 of Intermediate-30 by using methyl4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoate(1.00 g, 2.19 mmol), methanol (20 mL) and HCl (10 mL) to afford 1.00 gof desired product.

Step-3:—Preparation of methyl4-(3-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoate

The title compound was prepared by following the procedure as describedfor step-2 of Intermediate-30 by using methyl4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoatehydrochloride (0.250 g, 0.5 mmol), cyclopropane carbonyl chloride (0.108g, 1.0 mmol), DIPEA (2.0 mL), THF (10 mL) to afford 0.200 g of desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 1.05 (s, 2H), 1.60 (m, 2H), 3.14(m, 1H), 3.87 (s, 3H), 4.33 (d, J=5.7 Hz, 2H), 7.41-7.61 (m, 4H),8.11-8.17 (m, 3H), 8.69 (m, 1H), 12.65 (br s, 1H); MS (m/z): 427.14(M+H)⁺.

Intermediate-434-(3-(2-Chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methoxybenzamide

The title compound was prepared by following the procedure as describedfor step-6 of Intermediate-26 by using methyl4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-1 of Intermediate-34, 0.100 g, 0.20 mmol),4-fluoro-3-(trifluoromethyl)aniline (0.044 g, 0.34 mmol), trimethylaluminium (2M solution in toluene) (1.0 mL) and dry toluene (8.0 mL) toafford 0.020 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.94 (s,3H), 3.78 (t, 1H), 7.52 (t, 2H), 7.71-7.82 (m, 3H), 8.03 (d, J=6.6 Hz,2H), 10.38 (s, 1H), 12.69 (br s, 1H).

Intermediate-44 tert-Butyl 2-(2,6-dichlorophenyl)hydrazinecarboxylate

Step-1:—Preparation of (2,6-dichlorophenyl)hydrazine hydrochloride

To a cold solution of 2,6-dichloroaniline (10.0 g, 61.72 mmol) in conc.HCl was added aqueous solution of sodium nitrite (5.11 g, 74.00 mmol) at−15° C. The reaction mass was stirred at 0-10° C. for 15 minutes. Thereaction mass was filtered off to remove insolubles and stannouschloride in conc. HCl (34.7 g, 150 mmol) was added to the filtrate. Thereaction mass was further stirred at −15° C. for 30 min and filtered toafford 15.00 g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ7.18-7.28 (m, 1H), 7.39-7.52 (m, 2H), 10.30 (br s, 3H); MS (m/z): 176.90(M)⁺.

Step-2:—Preparation of tert-butyl2-(2,6-dichlorophenyl)hydrazinecarboxylate

To the cold solution of (2,6-dichlorophenyl)hydrazine hydrochloride(15.0 g, 84.0 mmol) in THF (50 mL) was added aqueous solution of K₂CO₃(23.3 g, 169 mmol) and BOC anhydride solution in THF (20.3 g, 93.00mmol) at 0° C. The reaction mass was stirred at RT for 12 h. Thereaction mass was quenched in water and extracted with DCM. The organiclayer was dried over anhydrous sodium sulphate and concentrated. Theobtained solid was washed with pentane to afford 6.5 g of desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 1.34 (s, 9H), 6.85 (m, 1H), 7.06(s, 1H), 7.27 (d, J=7.8 Hz, 2H), 9.01 (s, 1H); MS (m/z): 276.88 (M−H)⁻.

Intermediate-451-(2,6-Dichlorophenyl)-3-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one

Step-1:—Preparation of 3-methoxy-4-nitrobenzamide

To a cold solution of 3-methoxy-4-nitrobenzoic acid (2.0 g, 10.10 mmol)in THF (25 mL) was added oxalyl chloride (1.1 mL, 12.1 mmol) and DMF(2-3 drop) at 0° C. The reaction mixture was stirred at RT for 2 h andconcentrated. The solution of the concentrated mass in THF (15 mL) wastreated with ammonia gas (purged through reaction mass) at 0° C. and thereaction mixture was stirred at RT for 1 h. The reaction mass wasdiluted with ethyl acetate, washed with water, dilute HCl and brine. Theorganic layer was separated, dried, filtered and concentrated. Theconcentrate was used for the next step without further purification. ¹HNMR (300 MHz, DMSO d₆): δ 3.97 (s, 3H), 7.56 (d, J=8.1 Hz, 1H),7.72-7.75 (m, 2H), 7.94 (d, J=8.4 Hz, 1H), 8.25 (s, 1H); MS (m/z):195.98 (M)⁻.

Step-2:—Preparation of 3-methoxy-4-nitrobenzoyl isocyanate

To a solution of 3-methoxy-4-nitrobenzamide (1.00 g, 5.10 mmol) in EDC(10 mL) was added oxalyl chloride (0.64 g, 6.12 mmol). The reaction masswas refluxed for 24 h. Excess of solvent was removed under vacuum toafford 1.0 g of desired product.

Step-3:—Preparation of tert-butyl2-(2,6-dichlorophenyl)-2-((3-methoxy-4-nitrobenzoyl)carbamoyl)hydrazinecarboxylate

To a solution of tert-butyl 2-(2,6-dichlorophenyl)hydrazinecarboxylate(Intermediate-44, 1.2 g, 4.5 mmol) in DCM (20 mL) was added3-methoxy-4-nitrobenzoyl isocyanate (1.0 g, 4.5 mmol). The reaction masswas stirred at RT for 2 h. Excess of solvent was removed under vacuum toafford 1.5 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.35 (s,9H), 3.97 (s, 3H), 7.89 (m, 1H), 7.27-7.35 (m, 2H), 7.55 (d, 1H),7.62-7.75 (m, 1H), 7.94 (d, 1H), 8.26 (s, 1H), 9.03 (s, 1H); MS (m/z):496.78 (M−H)⁻.

Step-4:—Preparation of1-(2,6-dichlorophenyl)-3-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one

To a solution of tert-butyl2-(2,6-dichlorophenyl)-2-((3-methoxy-4-nitrobenzoyl)carbamoyl)hydrazinecarboxylate(1.0 g, 2.002 mmol) in DCM (20 mL) was added trifluoro acetic acid (2.0mL). The reaction mass was stirred at RT for 2-3 h. Excess of solventwas removed at low temperature. The reaction mass was quenched in iceand filter off to afford 0.200 g of desired product. ¹H NMR (300 MHz,DMSO d₆): δ 3.98 (s, 3H), 7.56-7.62 (m, 2H), 7.69-7.75 (m, 3H), 8.02 (d,J=8.4 Hz, 1H), 11-12 (br s, 1H); MS (m/z): 382.07 (M+H)⁺.

Step-5:—Preparation of3-(4-amino-3-methoxyphenyl)-1-(2,6-dichlorophenyl)-1H-1,2,4-triazol-5(4H)-one

To a solution of1-(2,6-dichlorophenyl)-3-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one(0.200 g, 0.52 mmol) in methanol (10 mL) was added iron powder (0.060 g,1.84 mmol) and conc. HCl (2 mL). The reaction mixture was stirred at RTfor 2 h. The reaction mass was quenched in water, basified withsaturated sodium bicarbonate solution and extracted with DCM. Theorganic layer was dried over anhydrous sodium sulphate and concentratedto afford 0.150 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.80(s, 3H), 5.34 (s, 2H), 6.66 (d, J=7.8 Hz, 1H), 7.18-7.21 (m, 2H), 7.58(m, 1H), 7.69 (d, J=7.8 Hz, 2H), 12.27 (s, 1H); MS (m/z): 351.05 (M)⁺.

Step-6:—Preparation of1-(2,6-dichlorophenyl)-3-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one

To a solution of3-(4-amino-3-methoxyphenyl)-1-(2,6-dichlorophenyl)-1H-1,2,4-triazol-5(4H)-one(0.300 g, 0.85 mmol) in acetonitrile (20 mL) was added PTSA (0.488 g,2.56 mmol). The reaction mixture was stirred at RT for 2 h, followed byaddition of aqueous solution of NaNO₂ (0.118 g, 1.170 mmol) and KI(0.284 g, 1.70 mmol). The reaction mixture was stirred at RT for 2 h.The reaction mass was concentrated and quenched in water. The reactionmass was washed with sodium metabisulphite solution and extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulphate and concentrated to afford 0.220 g of desired product. ¹H NMR(300 MHz, DMSO d₆): δ 3.89 (s, 3H), 7.23 (d, J=7.8 Hz, 1H), 7.40 (s,1H), 7.61 (m, 1H), 7.71-7.73 (m, 2H), 7.92 (d, J=8.4 Hz, 1H), 12.74 (s,1H); MS (m/z): 461.93 (M)⁺.

Intermediate-46 Methyl4-(1-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-methoxybenzoate

Step-1:—Preparation of methyl 2-methoxy-4-methylbenzoate

To a solution of 2-hydroxy-4-methylbenzoic acid (10.00 g, 65 mmol) inDMF (10 mL) was added K₂CO₃ (13.6 g, 98 mmol). The reaction mixture wasstirred at 60° C. for 1 h. Methyl iodide (14.0 g, 98 mmol) was added tothe reaction mixture and was stirred at 60° C. for 18 h. The reactionmass was quenched in water and concentrated. The reaction mass wasextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulphate and concentrated to afford 10.00 g of desired product.¹H NMR (300 MHz, DMSO d₆): δ 2.34 (s, 3H), 3.74 (s, 3H), 3.79 (s, 3H),6.81 (d, J=7.2 Hz, 1H), 6.97 (s, 1H), 7.56 (d, J=7.8 Hz, 1H); MS (m/z):180.95 (M+H)⁺.

Step-2:—Preparation of methyl 4-(bromomethyl)-2-methoxybenzoate

To a solution of methyl 2-methoxy-4-methylbenzoate (10.00 g, 55 mmol) inCCl₄ (150 mL) were added NBS (11.8 g, 66 mmol) and AIBN (0.100 g). Thereaction mixture was refluxed for 18 h. The reaction mass was dilutedwith diethyl ether and washed with 25% NaOH solution. The organic layerwas dried over anhydrous sodium sulphate and concentrated to afford10.00 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.77 (m, 6H),4.68 (s, 2H), 7.06 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.61 (d, J=7.8 Hz,1H); MS (m/z): 259.13 (M)⁺.

Step-3:—Preparation of methyl 4-formyl-2-methoxybenzoate

To a solution of sodium methoxide (0.260 g, 4.82 mmol) in methanol (200mL) was added nitromethane (4.03 g, 11.58 mmol) under nitrogenatmosphere and the reaction mixture was stirred and reflux for 30minutes. Methyl 4-(bromomethyl)-2-methoxybenzoate (10.00 g, 9.65 mmol)in methanol was added and the reaction mixture was refluxed for 7-8 h.The reaction mass was concentrated and diluted with CHCl₃. The dilutedreaction mass was washed with 2N NaOH solution. The organic layer wasdried over anhydrous sodium sulphate and concentrated to afford 6.00 gof desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.83 (m, 6H), 7.36 (d,J=6.6 Hz, 2H), 7.79 (d, J=7.8 Hz, 1H), 10.04 (s, 1H).

Step-4:—Preparation of 3-methoxy-4-(methoxycarbonyl)benzoic acid

To a cold solution of methyl 4-formyl-2-methoxybenzoate (6.0 g, 7.73mmol) in acetone (50 mL) was added aqueous sulphamic acid solution (4.5g, 11.59 mmol) and aqueous sodium chlorite solution (4.04 g, 11.59 mmol)at 0-5° C. The reaction mixture was stirred at RT for 3-4 h. Excess ofsolvent was removed under vacuum. The obtained residue was diluted withwater and basified with saturated sodium bicarbonate solution. Theaqueous layer was washed with diethyl ether to remove organic impuritiesand the obtained aqueous layer was again acidified with conc.HCl. Thesolid obtained was filtered and suck dried to afford 2.00 g of desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 3.80 (s, 3H), 3.87 (s, 3H),7.55-7.59 (m, 2H), 7.70 (d, J=7.8 Hz, 1H), 13.37 (s, 1H); MS (m/z):210.97 (M+H)⁺.

Step-5:—Preparation of methyl 4-carbamoyl-2-methoxybenzoate

The title compound was prepared according to the procedure described instep-2 of Intermediate-26 by using 3-methoxy-4-(methoxycarbonyl)benzoicacid (2.00 g, 9.52 mmol), oxalyl chloride (1.02 g, 11.42 mmol), ammoniagas and THF (25 mL) to afford 1.40 g of the desired product. ¹H NMR (300MHz, DMSO d₆): δ 3.79 (s, 3H), 3.87 (s, 3H), 7.49 (d, J=8.4 Hz, 1H),7.57 (s, 2H), 7.68 (d, J=7.8 Hz, 1H), 8.14 (s, 1H); MS (m/z): 209.99(M)⁺.

Step-6:—Preparation of methyl 4-(isocyanatocarbonyl)-2-methoxybenzoate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using methyl 4-carbamoyl-2-methoxybenzoate(1.4 g, 6.69 mmol), oxalyl chloride (0.72 mL, 8.03 mmol) and EDC (10 mL)to afford 1.00 g of the desired product.

Step-7:—Preparation of tert-butyl2-(2,6-dichlorophenyl)-2-((3-methoxy-4-(methoxycarbonyl)benzoyl)carbamoyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-1 of Intermediate-9 by using methyl4-(isocyanatocarbonyl)-2-methoxybenzoate (0.84 g, 3.61 mmol), tert-butyl2-(2,6-dichlorophenyl)hydrazinecarboxylate (Intermediate-44, 1.0 g, 3.61mmol) and DCM (20 mL) to afford 1.50 g of the desired product. ¹H NMR(300 MHz, DMSO d₆): δ 1.35 (s, 9H), 3.80 (s, 3H), 3.87 (s, 3H),7.28-7.42 (m, 6H), 9.57 (s, 1H), 10.85 (s, 1H); MS (m/z): 511.73 (M)⁺.

Step-8:—Preparation of methyl4-(1-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-methoxybenzoate

The title compound was prepared according to the procedure described instep-2 of Intermediate-9 by using tert-butyl2-(2,6-dichlorophenyl)-2-((3-methoxy-4-(methoxycarbonyl)benzoyl)carbamoyl)hydrazinecarboxylate(1.5 g, 2.9 mmol), DCM (20 mL) and trifluoro acetic acid (2.0 mL) toafford 0.600 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.80 (s,3H), 3.80 (s, 3H), 7.49-7.71 (m, 3H), 7.74-7.79 (m, 3H), 12.85 (s, 1H);MS (m/z): 393.95 (M)⁺.

Intermediate-47 2-Fluoro-4-iodobenzoyl isocyanate

Step-1:—Preparation of 2-fluoro-4-iodobenzoic acid

A solution of sodium dichromate (25.2 g, 84.0 mmol) in acetic acid (100mL) was stirred for 10 min, followed by addition of2-fluoro-4-iodo-1-methylbenzene (10.0 g, 42 mmol). The reaction mixturewas stirred for 5 min followed by slow addition of conc.H₂SO₄ (60 mL)for 1-2 h. The reaction mixture stirred at 90-100° C. for 7-8 h. Thereaction mixture was cooled and quenched with ice water. The reactionmass was extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulphate and concentrated to afford 5.0 g of thedesired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.58 (t, J=8.4 Hz, 1H),7.67 (d, J=7.5 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 13 (br s, 1H); MS (m/z):264.99 (M−H)⁻.

Step-2:—Preparation of 2-fluoro-4-iodobenzamide

The title compound was prepared according to the procedure described instep-2 of Intermediate-26 by using 2-fluoro-4-iodobenzoic acid (5.00 g,18.0 mmol), oxalyl chloride (2.0 mL, 22.0 mmol), ammonia gas, DCM (100mL) and THF (100 mL) to afford 2.00 g of the desired product. ¹H NMR(300 MHz, DMSO d₆): δ 7.40 (t, J=7.8 Hz, 1H), 7.63-7.76 (m, 1H); MS(m/z): 266.19 (M+H)⁺.

Step-3:—Preparation of 2-fluoro-4-iodobenzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using 2-fluoro-4-iodobenzamide (0.500 g, 1.8mmol), oxalyl chloride (0.285 g, 2.2 mmol) and EDC (10 mL) to afford0.350 g of the desired product.

Intermediate-48N-(4-Chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide

Step-1:—Preparation of 5-(aminomethyl)-2-chlorobenzoic acidhydrochloride

To a solution of 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoicacid (step-1 of Intermediate-26, 10.0 g, 35.50 mmol) in methanol (100mL) was added conc. HCl (10 mL). The reaction mixture was refluxed for18 h. The reaction mixture was concentrated and crude reaction mixturewas used for next step.

Step-2:—Preparation of methyl 5-(aminomethyl)-2-chlorobenzoate

To a solution of 5-(aminomethyl)-2-chlorobenzoic acid hydrochloride(17.0 g, 76.5 mmol) in methanol (200 mL) was added conc.H₂SO₄ (15 mL).The reaction mixture was refluxed for 15 h. The reaction mixture wasconcentrated and water was added. The aq. solution was basified withsodium bicarbonate. The reaction mixture was extracted with 10% MeOH:DCMand concentrated to afford 15.0 g of desired product. ¹H NMR (300 MHz,DMSO d₆): δ 2.1 (br s, 2H), 3.73 (s, 2H), 3.85 (s, 3H), 7.50 (s, 2H),7.77 (s, 1H); MS (m/z): 200.05 (M+H)⁺.

Step-3:—Preparation of methyl2-chloro-5-(cyclopropanecarboxamidomethyl)benzoate

To a solution of methyl 5-(aminomethyl)-2-chlorobenzoate (15.0 g, 75mmol) in dry THF (150 mL) was added DIPEA (15 mL) under nitrogenatmosphere. Cyclopropanecarbonyl chloride was added to the reactionmixture at 10° C. and (11.81 g, 113 mmol). The reaction mixture wasstirred at RT for 5-6 h. The reaction mixture was quenched with icewater and extracted with ethyl acetate. The organic layer was washedwith dilute HCl, followed with sodium bicarbonate solution andconcentrated to afford 10.0 g of desired product. ¹H NMR (300 MHz, DMSOd₆): δ 0.69 (m, 4H), 1.59 (m, 1H), 3.86 (s, 3H), 4.29 (d, J=6.0 Hz, 2H),7.43 (d, J=6.6 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.67 (s, 1H), 8.64 (brs, 1H); MS (m/z): 268.16 (M+H)⁺.

Step-4:—Preparation of 2-chloro-5-(cyclopropanecarboxamidomethyl)benzoicacid

To a solution of methyl2-chloro-5-(cyclopropanecarboxamidomethyl)benzoate (10.0 g, 30 mmol) inTHF:methanol (10:20 mL) was added aqueous solution of NaOH (6.0 g, 140mmol). The reaction mixture was refluxed for 3-5 h. The reaction mixturewas concentrated, diluted with water and acidified with dilute HCl. Thereaction mixture was extracted with 10% MeOH:DCM and concentrated toafford 4.0 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.67 (m,4H), 1.59 (m, 1H), 4.28 (d, J=6.0 Hz, 2H), 7.37-7.50 (m, 2H), 7.65 (s,1H), 8.64 (m, 1H), 13.40 (br s, 1H).

Step-5:—Preparation of N-(3-amino-4-chlorobenzyl)cyclopropanecarboxamide

To a solution of 2-chloro-5-(cyclopropanecarboxamidomethyl)benzoic acid(5.0 g, 19 mmol) in conc.H₂SO₄ (30 mL) was added NaN₃ (1.4 g, 21 mmol)lotwise at 50° C. The reaction mixture was stirred at 50° C. for 18 h.The reaction mass was quenched with ammonia and ice water. The solidobtained was filtered and suck dried to afford 3.0 g of desired product.¹H NMR (300 MHz, DMSO d₆): δ 0.66 (m, 4H), 1.56 (m, 1H), 4.12 (d, J=6.0Hz, 2H), 5.27 (s, 2H), 6.41 (d, J=6.9 Hz, 1H), 6.61 (s, 1H), 7.10 (d,J=8.4 Hz, 1H), 8.48 (m, 1H); MS (m/z): 225.22 (M+H)⁺.

Step-6:—Preparation ofN-(4-chloro-3-hydrazinylbenzyl)cyclopropanecarboxamide

To a cold solution of N-(3-amino-4-chlorobenzyl)cyclopropanecarboxamide(2.00 g, 8.90 mmol) in conc. HCl (25 mL) was added aqueous solution ofsodium nitrite (0.676 g, 9.7 mmol) at −20° C. to −25° C. The reactionmass was stirred at −20° C. to −25° C. for 30 min, followed by additionof stannous chloride solution (5.0 g, 22.2 mmol) in conc. HCl slowly.The reaction mass was stirred at −20° C. to −25° C. for 1 h. Thereaction mass was basified with aqueous NaOH at below 0° C. The reactionmass was diluted with water, extracted with 10% MeOH:DCM andconcentrated to afford 1.6 g of desired product. ¹H NMR (300 MHz, DMSOd₆): δ 0.66 (m, 4H), 1.58 (m, 1H), 4.10 (s, 2H), 4.18 (d, J=5.4 Hz, 2H),6.47 (m, 2H), 7.11 (m, 2H), 8.51 (br s, 1H); MS (m/z): 240.05 (M+H)⁺.

Step-7:—Preparation of tert-butyl2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)hydrazinecarboxylate

To a cold solution ofN-(4-chloro-3-hydrazinylbenzyl)cyclopropanecarboxamide (1.60 g, 6.69mmol) in acetonitrile (20 mL) was added aqueous solution of Na₂CO₃ (1.06g, 10.04 mmol) and BOC anhydride (1.06 g, 7.36 mmol). The reaction masswas stirred at RT for 12 h. The reaction mass was quenched in water andextracted with ethyl acetate and concentrated to afford 1.00 g of thecrude product which was further purified by column chromatography usingbasic alumina eluting with 0.3% MeOH:DCM to afford 0.900 g of pureproduct. ¹H NMR (300 MHz, DMSO d₆): δ 0.63 (m, 4H), 1.40 (s, 9H), 1.54(m, 1H), 4.15 (d, J=6.0 Hz, 2H), 6.59 (m, 2H), 7.17 (d, J=7.8 Hz, 1H),7.31 (s, 1H), 8.51 (m, 1H), 8.87 (s, 1H); MS (m/z): 338.41 (M−H)⁻.

Step-8:—Preparation of tert-butyl2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-2-((2-fluoro-4-iodobenzoyl)carbamoyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-1 of Intermediate-9 by using 2-fluoro-4-iodobenzoyl isocyanate(Intermediate-47, 0.500 g, 1.71 mmol), tert-butyl2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)hydrazinecarboxylate (0.582 g, 1.71 mmol) and DCM (20 mL) to afford 0.200 g ofthe desired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.69 (m, 4H), 1.42 (s,9H), 1.56 (m, 1H), 4.17 (d, J=5.7 Hz, 2H), 6.58-6.63 (m, 2H), 7.18 (d,J=8.1 Hz, 1H), 7.30 (m, 3H), 7.63-7.79 (m, 2H), 8.53 (m, 1H), 8.90 (s,1H); MS (m/z): 630.85 (M+H)⁺.

Step-9:—Preparation ofN-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide

To a solution of tert-butyl2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-2-((2-fluoro-4-iodobenzoyl)carbamoyl)hydrazinecarboxylate(0.200 g, 0.31 mmol) in DCM (10 mL) was added trifluoro acetic acid (1.0mL). The reaction mass was stirred at RT for 12 h and refluxed for 15 h.The reaction mass was cooled to RT, basified with NaHCO₃ (pH=8),extracted with DCM and concentrated to afford 0.110 g of desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 0.68 (m, 4H), 1.59 (m, 1H), 4.32(d, J=5.7 Hz, 2H), 7.38 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.51-7.63 (m,2H), 7.75 (d, J=8.1 Hz, 1H), 7.88 (d, J=10.2 Hz, 1H), 8.68 (m, 1H),12.43 (br s, 1H); MS (m/z): 513.01 (M+H)⁺.

Intermediate-49 4-Chloro-1-ethynyl-2-fluorobenzene

Step-1:—Preparation of ((4-chloro-2-fluorophenyl)ethynyl)trimethylsilane

To a solution of 4-chloro-2-fluoro-1-iodobenzene (2.0 g, 7.8 mmol) inDMSO (10 mL) was added ethynyl(trimethyl)silane (1.14 g, 11.0 mmol),copper iodide (0.029 g, 0.15 mmol), bis(triphenylphosphine)palladium(II) chloride (0.218 g, 0.3 mmol) and TEA (1 mL). The reactionmass was stirred at RT for 4-5 h. The reaction mass quenched in water,passed through celite bed and extracted with ethyl acetate andconcentrated to afford 1.0 g of desired product.

Step-2:—Preparation of 4-chloro-1-ethynyl-2-fluorobenzene

To a solution of ((4-chloro-2-fluorophenyl)ethynyl)trimethylsilane (1.0g, 4.42 mmol) in DCM (20 mL) was added TBAF (catalytic) and reactionmixture was stirred for 1-2 h at RT. The reaction mass was quenched inwater, extracted with DCM and concentrated to afford 0.900 g of thecrude product which was further purified by column chromatographyeluting with pet. ether to afford to afford 0.500 g of pure product. ¹HNMR (300 MHz, DMSO d₆): δ 4.60 (s, 1H), 7.32 (d, J=8.1 Hz, 1H),7.56-7.61 (m, 2H).

Intermediate-50 1-Ethynyl-3-(trifluoromethyl)benzene

Step-1:—Preparation oftrimethyl((3-(trifluoromethyl)phenyl)ethynyl)silane

To a solution of 1-iodo-3-(trifluoromethyl)benzene (1.0 g, 3.6 mmol) inethyl acetate (20 mL) was added ethynyl(trimethyl)silane (0.540 g, 5.5mmol), copper iodide (0.042 g, 0.22 mmol), bis(triphenylphosphine)palladium(II) chloride (0.129 g, 0.18 mmol) and TEA (2.2 mL, 14.7 mmol).The reaction mass stirred at 50-60° C. for 24 h. The reaction mass wasquenched in water, extracted with ethyl acetate and concentrated toafford 0.500 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.26 (s,9H), 7.44 (t, J=7.8 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.2 Hz,1H), 7.72 (s, 1H).

Step-2:—Preparation of 1-ethynyl-3-(trifluoromethyl)benzene

To a solution of trimethyl((3-(trifluoromethyl)phenyl)ethynyl)silane(0.500 g, 2.06 mmol) in ethanol (10 mL) was added potassium carbonate(0.253 g, 1.8 mmol) and the reaction mixture was stirred at RT for 18 h.The reaction mass was quenched in water, neutralized with dil. HCl andextracted with hexane and concentrated to afford 0.200 g of the crudeproduct which was further purified by column chromatography using silica(60-120 mesh) eluting with pet. ether to afford 0.500 g of pure product.¹H NMR (300 MHz, DMSO d₆): δ 4.41 (s, 1H), 7.64 (d, J=7.5 Hz, 1H),7.77-7.81 (m, 3H).

Intermediate-51 6-Chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate

Step-1:—Preparation of ethyl 6-chloro-2-fluoro-3-formylbenzoate

To a cold solution of ethyl 2-chloro-6-fluorobenzoate (0.500 g, 24.7mmol) in THF (35 mL) was added LDA (6.6 g, 61.8 mmol) at −78° C. Thereaction mixture was stirred for 2 h at same temperature, followed byaddition of DMF (2.7 g, 37 mmol). The reaction mixture was furtherstirred for 2 h at same temperature. The reaction mass was quenched indilute HCl, extracted with ethyl acetate and concentrated to affordcrude product which was further purified by column chromatographyeluting with EtOAC: pet.ether to afford 2.00 g of pure product. ¹H NMR(300 MHz, DMSO d₆): δ 1.31 (t, 3H), 4.42 (q, 2H), 7.94-7.99 (m, 2H),10.14 (s, 1H).

Step-2:—Preparation of ethyl6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate

To a solution of ethyl 6-chloro-2-fluoro-3-formylbenzoate (1.1 g, 4.0mmol) in MeOH (5 mL) was added (aq. solution) hydroxylamine (4 mL) andthe reaction mixture was heated at 60° C. for 2-3 h. The reaction masswas concentrated and extracted with EtOAC. The organic layer was washedwith brine and concentrated to afford 0.900 g of the product. ¹H NMR(300 MHz, DMSO d₆): δ 1.31 (t, J=6.9 Hz, 3H), 4.40 (q, J=6.6 Hz, 2H),7.47 (d, J=9.0 Hz, 1H), 7.86 (t, J=8.1 Hz, 1H), 8.20 (s, 1H), 11.89 (brs, 1H).

Step-3:—Preparation of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate

To a solution of ethyl6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (0.800 g, 3.26 mmol)in MeOH (5 mL) was added Zn (0.850 g, 13.06 mmol), followed by dropwiseaddition of conc. HCl (catalytic) and the reaction mixture was heated at60° C. for 2-3 h. Excess of solvent was removed under vacuum and theresidue was diluted with water and basified with NaHCO₃, extracted withEtOAc and concentrated to afford 0.600 g of the product. ¹H NMR (300MHz, DMSO d₆): δ 1.31 (t, J=7.2 Hz, 3H), 3.76 (s, 2H), 4.38 (q, J=6.9Hz, 2H), 7.41 (d, J=8.1 Hz, 1H), 7.65 (t, J=8.1 Hz, 1H).

Step-4:—Preparation of ethyl6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate

To a solution of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (0.540g, 2.5 mmol) in THF (5 mL) was added pivaloyl chloride (0.335 g, 2.79mmol) and TEA (0.1 mL) and the reaction mixture was stirred for 2-3 h atRT. Excess of solvent was removed under vacuum and the residue wasdiluted with water, extracted with EtOAC and concentrated to afford0.500 g of the product. ¹H NMR (300 MHz, DMSO d₆): δ 1.11 (s, 9H), 1.31(t, J=7.5 Hz, 3H), 4.26 (d, J=5.1 Hz, 2H), 4.39 (q, J=6.6 Hz, 2H),7.33-7.43 (m, 2H), 8.13 (m, 1H).

Step-5:—Preparation of 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoicacid

The title compound was prepared according to the procedure described instep-4 of Intermediate-48 by using ethyl6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (0.800 g) THF:methanol(2:2 mL) and aqueous solution of NaOH (1.0 g) to afford 0.500 g of theproduct. ¹H NMR (300 MHz, DMSO d₆): δ 1.11 (s, 9H), 4.26 (d, J=5.4 Hz,2H), 7.26-7.38 (m, 2H), 8.14 (m, 1H), 14.07 (br s, 1H).

Step-6:—Preparation of 6-chloro-2-fluoro-3-(pivalamidomethyl)benzamide

The title compound was prepared according to the procedure described instep-2 of Intermediate-26 by using6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (0.400 g, 1.39 mmol),THF (25 mL), oxalyl chloride (0.14 mL, 1.67 mmol) and ammonia gas toafford 0.220 g of the product. ¹H NMR (300 MHz, DMSO d₆): δ 1.12 (s,9H), 4.25 (d, J=5.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz,1H), 7.82 (s, 1H), 8.12 (br s, 2H); MS (m/z): 287.01 (M+H⁺).

Step-7:—Preparation of 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoylisocyanate

To a solution of 6-chloro-2-fluoro-3-(pivalamidomethyl)benzamide (0.300g, 1.04 mmol) in EDC (10 mL) was added oxalyl chloride (0.11 mL, 1.25mmol). The reaction mass was heated at 60-70° C. for 4-5 h. Excess ofsolvent was removed under vacuum to afford 1.0 g of desired product.

Intermediate-52 tert-Butyl 2-(3,4-dichlorophenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using (3,4-dichlorophenyl)hydrazinehydrochloride (1.00 g, 4.6 mmol), BOC anhydride (1.22 g, 5.6 mmol),Na₂CO₃ (1.24 g, 11.7 mmol), acetonitrile (20 mL) and water (10 mL) toafford 0.700 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.40 (s,9H), 6.62 (d, J=8.7 Hz, 1H), 6.77 (s, 1H), 7.34 (d, J=8.7 Hz, 1H), 8.02(s, 1H), 8.91 (s, 9H).

Intermediate-53 tert-Butyl2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using 4-(trifluoromethyl)phenylhydrazinehydrochloride (1.00 g, 5.6 mmol), BOC anhydride (1.46 g, 6.8 mmol),Na₂CO₃ (0.900 g, 8.5 mmol), acetonitrile (20 mL) and water (10 mL) toafford 0.600 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.41 (s,9H), 6.74 (d, J=8.7 Hz, 2H), 7.45 (d, J=9.0 Hz, 2H), 8.23 (s, 1H), 8.94(br s, 1H).

Intermediate-54 tert-Butyl 2-(2,4-difluorophenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using (2,4-difluorophenyl)hydrazinehydrochloride (1.00 g, 5.54 mmol), BOC anhydride (1.81 g, 8.31 mmol),Na₂CO₃ (1.46 g, 13.85 mmol), acetonitrile (20 mL) and water (10 mL) toafford 0.500 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.40 (s,9H), 6.70-6.72 (m, 1H), 6.90 (t, J=8.1 Hz, 1H), 7.07-7.14 (m, 1H), 7.47(s, 1H), 8.83 (br s, 1H).

Intermediate-55 tert-Butyl 2-(4-methoxyphenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using (4-methoxyphenyl)hydrazinehydrochloride (1.00 g, 5.72 mmol), BOC anhydride (1.8 g, 8.59 mmol),Na₂CO₃ (1.51 g, 14.31 mmol), acetonitrile (20 mL) and water (10 mL) toafford 0.400 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.39 (s,9H), 3.64 (s, 3H), 6.60 (d, J=7.8 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.18(br s, 1H), 8.68 (br s, 1H).

Intermediate-56 2-Fluoro-4-(trifluoromethyl)benzoyl isocyanate

Step-1:—Preparation of 2-fluoro-4-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure described instep-2 of Intermediate-26 by using 2-fluoro-4-(trifluoromethyl)benzoicacid (1.5 g), THF (25 mL), oxalyl chloride (0.5 mL) and ammonia gas toafford 1.35 g of the product. ¹H NMR (300 MHz, DMSO d₆): δ 7.65 (d,J=8.4 Hz, 1H), 7.77-7.84 (m, 3H), 7.96 (br s, 1H); MS (m/z): 208.06(M⁺).

Step-2:—Preparation of 2-fluoro-4-(trifluoromethyl)benzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using 2-fluoro-4-(trifluoromethyl)benzamide(0.200 g, 0.96 mmol), EDC (10 mL) and oxalyl chloride (0.1 mL, 1.15mmol) to afford 0.200 g of the product.

Intermediate-57 tert-Butyl2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate

Step-1:—Preparation of N-(3-amino-4-chloro-2-fluorobenzyl)pivalamide

To a solution of 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid(step-5 of Intermediate-51, 1.0 g, 3.48 mmol) in conc. sulphuric acid(10.0 mL) was added sodium azide (0.271 g, 4.18 mmol). The reaction masswas stirred at 50-60° C. for 18 h. The reaction mass was quenched inammonia solution (cold) and solid obtained was filtered and suck driedto afford 0.570 g of the product. ¹H NMR (300 MHz, DMSO d₆): δ 1.11 (s,9H), 4.21 (d, J=5.7 Hz, 2H), 5.30 (s, 2H), 6.39 (t, J=7.8 Hz, 1H), 7.00(d, J=8.4 Hz, 1H), 7.98 (m, 1H); MS (m/z): 259.12 (M+H⁺).

Step-2:—Preparation ofN-(4-chloro-2-fluoro-3-hydrazinylbenzyl)pivalamide

The title compound was prepared according to the procedure described instep-2 of Intermediate-7 by usingN-(3-amino-4-chloro-2-fluorobenzyl)pivalamide (0.500 g, 1.93 mmol),sodium nitrite (0.200 g, 2.90 mmol), stannous chloride.H₂O (4.84 g, 1.09mmol), conc. HCl (20.0 g) and water (3 mL) to afford 0.300 g of thedesired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.12 (s, 9H), 4.23 (d,J=5.4 Hz, 2H), 4.34 (br s, 2H), 5.91 (s, 1H), 6.65 (t, J=7.8 Hz, 1H),8.02 (m, 1H); MS (m/z): 274.08 (M+H⁺).

Step-3:—Preparation of tert-butyl2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl) hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by usingN-(4-chloro-2-fluoro-3-hydrazinylbenzyl)pivalamide (0.300 g, 1.09 mmol),BOC anhydride (0.360 g, 1.64 mmol), Na₂CO₃ (0.231 g, 2.18 mmol),acetonitrile (10 mL) and water (5 mL) to afford 0.150 g of desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 1.11 (s, 9H), 1.37 (s, 9H), 4.20(d, J=5.7 Hz, 2H), 6.64 (m, 1H), 7.06 (br s, 2H), 8.00 (br s, 1H), 8.98(s, 1H).

Intermediate-58 4-Chloro-2-fluorobenzoyl isocyanate

Step-1:—Preparation of 4-chloro-2-fluorobenzamide

The title compound was prepared according to the procedure described instep-2 of Intermediate-26 by using 4-chloro-2-fluoro benzoic acid (1.5g), THF (25 mL), oxalyl chloride (0.5 mL) and ammonia gas to afford 1.45g of the product. ¹H NMR (300 MHz, DMSO d₆): δ 7.36 (d, J=6.3 Hz, H),7.53 (dd, J=8.7 Hz, 1H), 7.64-7.76 (m, 3H).

Step-2:—Preparation of 4-chloro-2-fluorobenzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using 4-chloro-2-fluorobenzamide (0.200 g,1.26 mmol), EDC (10 mL) and oxalyl chloride (0.14 mL, 1.15 mmol) toafford 0.200 g of the product.

Intermediate-59 4-(Trifluoromethyl)benzoyl isocyanate

Step-1:—Preparation of 4-(trifluoromethyl)benzamide

To a cold solution of 4-(trifluoromethyl)benzonitrile (0.500 g, 2.92mmol) in DMSO (6.0 mL) was added H₂O₂ (50%) (5 mL) at 0° C., followed byportion-wise addition of K₂CO₃ (0.121 g, 0.87 mmol). The reaction masswas allowed to attain RT and stirred for 1 h. The reaction mass wasquenched in ice water and extracted with DCM and concentrated to afford0.300 g of product. ¹H NMR (400 MHz, DMSO d₆): δ 7.60 (br s, 1H), 7.82(d, J=7.5 Hz, 2H), 8.05 (d, J=6.6 Hz, 2H), 8.17 (br s, 1H); MS (m/z):190.11 (M+H⁺).

Step-2:—Preparation of 4-(trifluoromethyl)benzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using 4-(trifluoromethyl)benzamide (0.200 g,1.05 mmol), EDC (10 mL) and oxalyl chloride (0.15 mL, 1.58 mmol) toafford 0.200 g of the product.

Intermediate-60 tert-Butyl2-(5-(trifluoromethyl)pyridin-2-yl)hydrazinecarboxylate

Step-1:—Preparation of 2-hydrazinyl-5-(trifluoromethyl)pyridine

To a solution of 2-chloro-5-(trifluoromethyl)pyridine (1.5 g, 8.26 mmol)in ethanol (20.0 mL) was added hydrazinehydrate (1.21 g, 24.79 mmol).The reaction mass was refluxed for 5-6 h. The reaction mass wasconcentrated and quenched in ice water and solid obtained was filteredand suck dried to afford 0.700 g of the product. ¹H NMR (300 MHz, DMSOd₆): δ 4.32 (br s, 2H), 6.78 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H),8.25 (br s, 2H); MS (m/z): 178.15 (M+H⁺).

Step-2:—Preparation of tert-butyl2-(5-(trifluoromethyl)pyridin-2-yl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using2-hydrazinyl-5-(trifluoromethyl)pyridine (0.700 g, 3.95 mmol), BOCanhydride (1.3 g, 5.9 mmol), Na₂CO₃ (0.838 g, 7.90 mmol), acetonitrile(15 mL) and water (7 mL) to afford 0.500 g of desired product. ¹H NMR(400 MHz, DMSO d₆): δ 1.40 (s, 9H), 6.62 (d, J=8.8 Hz, 1H), 7.83 (dd,J=8.0 Hz, 1H), 8.37 (s, 1H), 8.95 (s, 1H), 9.01 (br s, 1H); MS (m/z):278.00 (M+H⁺).

Intermediate-61 tert-Butyl2-(6-(trifluoromethyl)pyridin-3-yl)hydrazinecarboxylate

Step-1:—Preparation of 5-hydrazinyl-2-(trifluoromethyl)pyridine

To a cold solution of 6-(trifluoromethyl)pyridin-3-amine (1.5 g, 9.25mmol) in 4N HCl (60.0 mL) was added aqueous solution of NaNO₂ (0.766 g,11.11 mmol) at 0° C. The reaction mass was stirred at same temperaturefor 30 minutes. The reaction mass was added to a solution of SnCl₂.H₂Oin 4N HCl at 80° C. and further continued stirring for 5-6 h at sametemperature. The reaction mass was cooled, basified and extracted withDCM. The organic layer was dried and concentrated to afford 0.700 g ofthe product. ¹H NMR (300 MHz, DMSO d₆): δ 4.29 (br s, 2H), 7.18 (dd,J=8.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.68 (s, 1H), 8.13 (d, J=2.4 Hz,1H); MS (m/z): 178.15 (M+H⁺).

Step-2:—Preparation of tert-butyl2-(6-(trifluoromethyl)pyridin-3-yl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using5-hydrazinyl-2-(trifluoromethyl)pyridine (0.700 g, 3.95 mmol), BOCanhydride (1.3 g, 5.9 mmol), Na₂CO₃ (0.838 g, 7.90 mmol), acetonitrile(15 mL) and water (7 mL) to afford 0.400 g of desired product. ¹H NMR(400 MHz, DMSO d₆): δ 1.31 (s, 9H), 7.10 (dd, J=8.0 Hz, 1H), 7.64 (d,J=8.6 Hz, 1H), 8.09 (d, J=2.3 Hz, 1H), 8.55 (br s, 1H), 9.08 (br s, 1H);MS (m/z): 278.05 (M+H⁺).

Intermediate-62 tert-Butyl 2-(4-chlorophenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using (4-chlorophenyl)hydrazinehydrochloride (1.5 g, 10.5 mmol), BOC anhydride (2.7 g, 12.6 mmol),Na₂CO₃ (2.23 g, 21.03 mmol), acetonitrile (20 mL) and water (10 mL) toafford 0.900 g of desired product.

Intermediate-633-(5-(Aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one

Step-1:—Preparation ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

To a solution of tert-butyl2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 1.00g, 3.63 mmol) in DCM (20 mL),2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3of Intermediate-26, 1.30 g, 4.03 mmol) was added and the reaction masswas stirred at RT for 2 h. After completion of reaction, excess ofsolvent was removed under reduced pressure to obtain 0.700 g of thecrude product. To a solution of obtained crude product in DCM (5.0 mL),TFA (5.0 mL) was added and the reaction mass was stirred at RT for 2-3h. Excess of the solvent was removed from the reaction mass underreduced pressure and the reaction mass was quenched in ice and filteredto obtain 0.700 g of the desired title product. ¹H NMR (300 MHz, DMSOd₆): δ 4.45 (d, 1H), 7.50 (d, J=4.8 Hz, 1H), 7.65-7.68 (m, 2H), 8.85 (d,J=6.6 Hz, 2H), 8.18 (d, J=6.3 Hz, 2H), 10.05 (s, 1H), 12.69 (s, 1H); MS(m/z): 463.17 (M−H)⁻.

Step-2:—Preparation of3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one

To a solution ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(0.400 g, 0.861 mmol) in THF (5.0 mL) was added KOH aqueous solution(0.096 g, 1.72 mmol) and the reaction mass was stirred at RT for 3-4 h.The reaction mass was quenched in water and extracted with ethyl acetateand concentrated to afford 0.200 g of the desired product.

Intermediate-64 tert-Butyl 2-Cyclohexyl hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using cyclohexyl hydrazine hydrochloride(1.00 g, 6.6 mmol), BOC anhydride (1.73 g, 7.9 mmol), Na₂CO₃ (1.75 g,16.6 mmol), acetonitrile (20 mL) and water (10 mL) to afford 0.500 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.95-1.02 (m, 2H),1.07-1.14 (m, 2H), 1.16 (s, 9H), 1.39-1.51 (m, 2H), 1.67-1.98 (m, 2H),2.61 (m, 1H), 8.16 (br s, 1H), 8.75 (br s, 1H). MS (m/z): 214.79 (M⁺).

Intermediate-65 3-((2,2,2-Trifluoroacetamido)methyl)-2,6-dimethylbenzoylisocyanate

Step-1:—Preparation of3((2,2,2-trifluoroacetamido)methyl)-2,6-dimethylbenzoic acid

To a solution of 2,6-dimethyl benzoic acid (6.8 g, 0.045 mmol) inconc.H₂SO₄ (100 mL), 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (7.1 g,0.049 mmol) was added and the reaction mixture was stirred at RT for 24h. After completion of the reaction, the reaction mass was quenched inice water and stirred for 15 minutes. The obtained solid product wasfiltered and dried to afford 7.0 g of the desired title product. ¹H NMR(300 MHz, DMSO d₆): δ 2.26 (s, 6H), 4.36 (t, J=12.3 Hz, 2H), 7.09 (m,1H), 7.15 (m, 1H), 9.89-9.94 (m, 1H).

Step-2:—Preparation of3-((2,2,2-trifluoroacetamido)methyl)-2,6-dimethylbenzamide

The title compound was prepared according to the procedure described instep-2 of Intermediate-26 by using3((2,2,2-trifluoroacetamido)methyl)-2,6-dimethylbenzoic acid (1.0 g),oxalyl chloride (1.0 mL), THF (50 mL) and ammonia gas to afford 0.800 gof the desired product.

Step-3:—Preparation of3-((2,2,2-trifluoroacetamido)methyl)-2,6-dimethylbenzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using3-((2,2,2-trifluoroacetamido)methyl)-2,6-dimethylbenzamide (1.0 g, 3.6mmol), oxalyl chloride and EDC (10 mL) to afford 0.900 g of the desiredproduct.

Intermediate-665-(3-(Aminomethyl)-2,6-dimethylphenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one

To a solution ofN-(3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)-2,2,2-trifluoroacetamide(Example-106, 0.800 g, 1.74 mmol) in THF (10 mL), aqueous solution ofKOH was added and the reaction mass was stirred at RT for 3-4 h. Aftercompletion of the reaction, the reaction mass was quenched with waterand extracted with ethyl acetate. The organic layer was separated, driedover anhydrous sodium sulphate and concentrated to afford 0.200 g of thedesired product. MS (m/z): 362.86 (M+H)⁺.

Intermediate-67 4-Iodobenzoyl isocyanate

The title compound was prepared according to the procedures described instep-2 and step-3 of Intermediate-26 by using 4-iodo benzoic acid (2.0g), oxalyl chloride (1.0 ml), ammonia gas, DCM (20 mL), THF (20 mL) toafford 1.5 g of the desired product. ¹H NMR (400 MHz, DMSO d₆): δ 7.17(br s, 1H), 7.64 (d, 2H), 8.01 (s, 2H); MS (m/z): 461.14 (M+H)⁺.

Intermediate-68N-(4-Chloro-2-fluoro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-83 by using tert-butyl2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate(Intermediate-57, 0.250 g), 4-iodobenzoyl isocyanate (Intermediate-67,0.250 g), DCM (10 mL) and trifluoro acetic acid (0.5 mL) to afford 0.150g of the desired product. ¹H NMR (400 MHz, DMSO d₆): δ 1.19 (s, 9H),4.30 (d, J=3.3 Hz, 2H), 7.39 (m, 1H), 7.45 (d, 1H), 7.62 (d, 2H), 7.90(d, J=3.6 Hz, 2H), 8.19 (t, 1H), 13.0 (br s, 1H); MS (m/z): 528.98(M+H)⁺.

Intermediate-695-((2,2,2-Trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate

Step-1:—Preparation of5((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoic acid

The title compound was prepared according to the procedure described instep-1 of Intermediate-26 by using 2-chloro-4-fluorobenzoic acid (5.0 g,0.002 mmol), 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (4.0 g, 0.002mmol) and conc.H₂SO₄ (50 mL) to afford 4.0 g of the desired product. ¹HNMR (400 MHz, DMSO d₆): δ 4.44 (d, J=12.0 Hz, 2H), 7.59 (m, 1H), 7.92(m, 1H), 10.0 (br s, 1H), 13.5 (br s, 1H).

Step-2:—Preparation of5((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzamide

The title compound was prepared according to the procedure described instep-2 of Intermediate-26 by using5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoic acid (1.0g), oxalyl chloride (1.0 mL), THF (50 mL) and ammonia gas to afford0.800 g of the desired product. ¹H NMR (400 MHz, DMSO d₆): δ 4.53 (m,2H), 7.43 (m, 1H) 7.44 (m, 2H), 7.48 (m, 1H), 10.0 (br s, 1H)); MS(m/z): 297.10 (M−H)⁻.

Step-3:—Preparation of5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzamide (1.0 g,3.6 mmol), oxalyl chloride (1.0 mL) and EDC (10 mL) to afford 0.750 g ofthe desired product.

Intermediate-705-(5-(Aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-2-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(Example-113, 0.100 g, 0.207 mmol), KOH (0.034 g, 0.622 mol), water (5mL) and THF (5.0 mL) to afford 0.080 g of the desired product.

Intermediate-71 tert-Butyl2-(4-chloro-3-fluorophenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using 4-chloro3-fluoro phenylhydrazinehydrochloride (1.00 g), BOC anhydride (1.5 g), Na₂CO₃ (0.900 g, 8.5mmol), acetonitrile (20 mL) and water (10 mL) to afford 0.600 g of thedesired product.

Intermediate-72 4,4-Dimethyl tert-butyl 2-cyclohexylhydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using 4,4-dimethylcyclohexylhydrazinehydrochloride (1.00 g), BOC anhydride (1.5 g), Na₂CO₃ (0.900 g, 8.5mmol), acetonitrile (20 mL) and water (10 mL) to afford 0.600 g of thedesired product.

Intermediate-735-(5-(Aminomethyl)-2-chlorophenyl)-2-(4,4-dimethylcyclohexyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-3-(4,5-dihydro-1-(4,4-dimethylcyclohexyl)-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(Example-117, 0.150 g, 0.348 mmol), KOH (0.039 g, 0.696 mol), water (2mL) and THF (5.0 mL) to afford 0.100 g of the desired product.

Intermediate-74 tert-Butyl 2-tert-butylhydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using tert-butylhydrazine (1.00 g), BOCanhydride (1.5 g), Na₂CO₃ (0.900 g, 8.5 mmol), acetonitrile (20 mL) andwater (10 mL) to afford 0.600 g of the desired product.

Intermediate-752-tert-Butyl-5-(5-(aminomethyl)-2-chlorophenyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(3-(1-tert-butyl-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-4-chlorobenzyl)-2,2,2-trifluoroacetamide(Example-120, 0.400 g, 1.062 mmol), KOH (0.119 g, 2.12 mmol), water (5mL) and THF (5.0 mL) to afford 0.300 g of the desired product.

Intermediate-765-(5-(Aminomethyl)-2-chlorophenyl)-2-(4-chloro-3-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-3-(1-(4-chloro-3-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(Example-116, 0.400 g, 0.890 mmol), KOH (0.099 g, 1.78 mmol), water (2mL) and THF (4.0 mL) to afford 0.300 g of the desired product.

Intermediate-775-(5-(Aminomethyl)-2-chloro-4-fluorophenyl)-2-(4,4-dimethylcyclohexyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-2-fluoro-5-(4,5-dihydro-1-(4,4-dimethylcyclohexyl)-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(Example-124, 1.0 g), KOH (1.0 g), water (5 mL) and THF (40.0 mL) toafford 0.700 g of the desired product.

Intermediate-785-(5-(Aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-chlorophenyl)-2H-1,2,4-triazol-3(4H)-one

Step-1:—Preparation ofN-(4-chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate(Intermediate-69, 0.400 g), tert-butyl2-(4-chlorophenyl)hydrazinecarboxylate (Intermediate-62, 0.400 g), DCM(20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.250 g of thedesired product.

Step-2:—Preparation of5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-chlorophenyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-2,2,2-trifluoroacetamide(0.160 g), KOH (0.050 g), water (2 mL) and THF (10.0 mL) to afford 0.070g of the desired product.

Intermediate-795-(5-(Aminomethyl)-2-chloro-4-methoxyphenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one

Step-1:—Preparation of5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-methoxybenzoic acid

The title compound was prepared according to the procedure described instep-1 of Intermediate-26 by using 2-chloro-4-methoxybenzoic acid (0.060g), 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (0.050 g) and H₂SO₄ (2mL) to afford 0.040 g of the desired product.

Step-2:—Preparation of5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-methoxybenzamide

The title compound was prepared according to the procedure described instep-2 of Intermediate-26 by using5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-methoxybenzoic acid (1.0g), oxalyl chloride (1.0 mL), THF (50 mL) and ammonia gas to afford0.800 g of the desired product.

Step-3:—Preparation of5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-methoxybenzoylisocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-methoxybenzamide (1.0 g,3.6 mmol), oxalyl chloride (1.0 mL) and EDC (10 mL) to afford 0.750 g ofthe desired product.

Step-4:—Preparation ofN-(4-chloro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-methoxybenzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-methoxybenzoylisocyanate (0.500 g), tert-butyl2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53,0.450 g), DCM (20 mL), and trifluoro acetic acid (5.0 mL) to afford0.180 g of the desired product.

Step-5:—Preparation of5-(5-(aminomethyl)-2-chloro-4-methoxyphenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-methoxybenzyl)-2,2,2-trifluoroacetamide(0.200 g), water (5 mL), KOH (0.200 g) and THF (10.0 mL) to afford 0.150g of the desired product.

Intermediate-80 tert-Butyl2-[4-fluoro-3-(trifluoromethyl)phenyl]hydrazinecarboxylate

Step 1:—Preparation of 1-(4-fluoro-3-(trifluoromethyl)phenyl)hydrazine

The title compound was prepared according to the procedure described instep-1 of Intermediate-61 by using 4-fluoro-3-(trifluoromethyl)aniline(3.0 g, 0.016 mmol), NaNO₂ (1.73 g, 0.025 mmol), SnCl₂.2H₂O (9.39 g,0.041 mmol) and conc. HCl (100 mL) to afford 2.0 g of the desiredproduct.

Step-2:—Preparation of tert-butyl2-[4-fluoro-3-(trifluoromethyl)phenyl]hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using1-(4-fluoro-3-(trifluoromethyl)phenyl)hydrazine (1.00 g), BOC anhydride(1.5 g), Na₂CO₃ (0.900 g, 8.5 mmol), acetonitrile (20 mL) and water (10mL) to afford 0.600 g of the desired product. ¹H NMR (300 MHz, CDCl₃): δ1.40 (s, 9H), 6.86-6.94 (m, 2H), 7.26-7.32 (m, 1H), 7.98 (s, 1H), 8.95(s, 1H); MS (m/z): 436.55 (M⁺H)⁺.

Intermediate-815-(5-(Aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one

Step-1:—Preparation ofN-(4-chloro-2-fluoro-5-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate(Intermediate-69, 0.400 g), tert-butyl2-[4-fluoro-3-(trifluoromethyl)phenyl]hydrazinecarboxylate(Intermediate-80, 0.400 g), DCM (20 mL) and TFA (5.0 mL) to afford 0.200g of the desired product.

Step-2:—Preparation of5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(0.400 g), KOH (0.100 g) and THF (10.0 mL) to afford 0.150 g of desiredproduct.

Intermediate-825-(5-(Aminomethyl)-2-chloro-4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)-2H-1,2,4-triazol-3(4H)-one

Step-1:—Preparation ofN-(4-chloro-2-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate(Intermediate-69, 0.350 g), tert-butyl2-[6-(trifluoromethyl)pyridin-3-yl]hydrazinecarboxylate(Intermediate-61, 0.350 g), DCM (20 mL) and TFA (5.0 mL) to afford 0.250g of the desired product.

Step-2:—Preparation of5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-2-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(0.500 g), KOH (0.200 g), water (5 mL) and THF (10.0 mL) to afford 0.150g of desired product.

Intermediate-83 tert-Butyl2-(2,4-dichloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate

Step-1:—Preparation of 2-(aminomethyl)-5-chloro-4-nitrobenzenamine

To a solution of 2-amino-4-chloro-5-nitrobenzamide (3.0 g, 13.7 mmol) indry THF (50 mL), borane dimethyl suphide complex (1.56 g, 20.6 mmol) wasadded at RT and the reaction mass was refluxed for 24 h. The reactionmass was cooled to RT and dilute HCl was added till it became acidic.Further, the reaction mixture was stirred for 1 h and then the reactionmixture was basified with dilute NaOH and extracted with ethyl acetate.The organic layer was separated, dried over anhydrous sodium sulphateand concentrated to afford 2.0 g of the desired product. ¹H NMR (300MHz, DMSO d₆): δ 3.58 (s, 2H), 6.72 (br s, 3H), 8.04 (br s, 1H); MS(m/z): 200.28 (M−H).

Step-2:—Preparation of N-(2-amino-4-chloro-5-nitrobenzyl)pivalamide

To a solution of 2-(aminomethyl)-5-chloro-4-nitrobenzenamine (2.5 g,12.25 mmol) in THF (35 mL), TEA (3.0 mL) and pivaloyl chloride (1.96 mL,14.7 mmol) were added and the reaction mass was stirred at RT for 5 h.The reaction mass was quenched with water and extracted with ethylacetate. The organic layer was washed with dilute HCl and dilute sodiumbicarbonate solution, separated, dried over anhydrous sodium sulphateand concentrated to afford 2.0 of the desired product. ¹H NMR (300 MHz,DMSO d₆): δ 1.12 (s, 9H), 4.30 (d, J=5.4 Hz, 2H), 7.81 (d, J=9.9 Hz,1H), 7.96 (d, J=6.3 Hz, 1H), 8.21 (m, 1H).

Step 3:—Preparation of N-(2,5-diamino-4-chlorobenzyl)pivalamide

To a solution of N-(2-amino-4-chloro-5-nitrobenzyl)pivalamide (2.0 g,6.9 mmol) in methanol (20 mL), Raney Ni (2.0 g) and hydrazine hydrate(5.0 mL) were added and the reaction mass was stirred at RT for 3 h.After the completion of the reaction, the reaction mass was filteredthrough celite pad and obtained filtrated was concentrated to afford 1.5g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.11 (s, 9H),3.97 (br d, 2H), 4.52 (br d, 2H), 5.44 (br s, 2H), 6.50 (d, J=11.4 Hz,2H), 7.88 (m, 1H).

Step-4:—Preparation ofN-(2,4-dichloro-5-hydrazinylbenzyl)-2,2-dimethylpropanamide

The title compound was prepared according to the procedure described instep-1 of Intermediate-61 by usingN-(2,5-diamino-4-chlorobenzyl)pivalamide (1.5 g, 5.8 mmol), NaNO₂ (0.481g, 6.9 mmol), SnCl₂.2H₂O (3.20 g, 14.5 mmol), conc. HCl (50 mL) toafford 1.0 g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.11(s, 9H), 4.44 (m, 2H), 6.53 (m, 1H), 7.18 (m, 1H), 7.99 (m, 1H), 10.23(s, 1H).

Step-5:—Preparation of tert-butyl2-(2,4-dichloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by usingN-(2,4-dichloro-5-hydrazinylbenzyl)-2,2-dimethylpropanamide (1.0 g, 3.6mmol), BOC anhydride (0.958 g, 4.39 mmol), Na₂CO₃ (0.776 g, 7.32 mmol),acetonitrile (10 mL) and water (5 mL) to afford 0.500 g of the desiredproduct.

Intermediate-84N-(2,4-Dichloro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-83 by using 4-iodobenzoyl isocyanate (Intermediate-67, 0.300 g,0.800 mmol), tert-butyl2-(2,4-dichloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-83, 0.397 g, 1.6 mmol), DCM (20 mL), trifluoroacetic acid (5.0 mL) to afford 0.150 g of the desired product. ¹H NMR(300 MHz, DMSO d₆): δ 1.09 (s, 9H), 4.31 (d, J=4.2 Hz, 2H), 7.40-7.58(m, 2H), 7.61-7.78 (m, 2H), 7.93-8.02 (br d, 2H), 8.17 (m, 1H).

Intermediate-85 tert-Butyl2-(3-chloro-4-fluorophenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using 1-(3-chloro-4-fluorophenyl)hydrazine(3.0 g, 0.015 mmol), BOC anhydride (3.6 g, 0.16 mmol), Na₂CO₃ (2.40 g,0.022 mmol), acetonitrile (30 mL) and water (5 mL) to afford 1.3 g ofthe desired product. ¹H NMR (300 MHz, CDCl₃): δ 1.38 (s, 9H), 6.60 (m,1H), 6.67 (m, 1H), 7.13-7.20 (m, 1H), 7.77 (s, 1H), 8.85 (s, 1H).

Intermediate-865-(5-(Aminomethyl)-2-chloro-4-fluorophenyl)-2-(3-chloro-4-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one

Step-1:—Preparation ofN-(4-chloro-5-(1-(3-chloro-4-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate(Intermediate-69, 0.300 g), tert-butyl2-(3-chloro-4-fluorophenyl)hydrazinecarboxylate (Intermediate-85, 0.300g), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.200 g ofthe desired product.

Step-2:—Preparation of5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(3-chloro-4-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-5-(1-(3-chloro-4-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-2,2,2-trifluoroacetamide(0.300 g), KOH (0.100 g), water (2 ml) and THF (10.0 mL) to afford 0.100g of the desired product.

Intermediate-87 tert-Butyl2-(3-chloro-4-methylphenyl)hydrazinecarboxylate

Step-1:—Preparation of 1-(3-chloro-4-methylphenyl)hydrazine

The title compound was prepared according to the procedure described instep-1 of Intermediate-61 by using 3-chloro-4-methylaniline (6.0 g,0.0420 mmol), NaNO₂ (8.56 g, 0.050 mmol), SnCl₂.2H₂O (23.7 g, 0.105mmol) and conc. HCl (100 mL) to afford 4.5 g of the desired product.

Step-2:—Preparation of tert-butyl 2-(3-chloro-4-methylphenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using 1-(3-chloro-4-methylphenyl)hydrazine(4.5 g, 0.028 mmol), BOC anhydride (6.8 g, 0.032 mmol), Na₂CO₃ (4.50 g,0.041 mmol), acetonitrile (30 mL) and water (5 mL) to afford 1.300 g ofthe desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.40 (s, 9H), 2.17 (s,3H), 6.53 (d, J=10.4 Hz, 1H), 6.63 (s, 1H), 7.08 (d, J=10.82 Hz, 1H),7.67 (s, 1H), 8.80 (s, 1H).

Intermediate-885-(5-(Aminomethyl)-2-chloro-4-fluorophenyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-triazol-3(4H)-one

Step-1:—Preparation ofN-(4-chloro-5-(1-(3-chloro-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate(Intermediate-69, 0.300 g), tert-butyl2-(3-chloro-4-methylphenyl)hydrazinecarboxylate (Intermediate-87, 0.300g), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.200 g ofthe desired product.

Step-2:—Preparation of5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(3-chloro-4-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-5-(1-(3-chloro-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-2,2,2-trifluoroacetamide(0.300 g), KOH (0.100 g), water (2 mL) and THF (10.0 mL) to afford 0.200g of the desired product.

Intermediate-89 tert-Butyl2-(2-chloro-4-fluoro-5-{[(trifluoroacetyl)amino]methyl}phenyl)hydrazinecarboxylate

Step-1:—Preparation ofN-(5-amino-4-chloro-2-fluorobenzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described instep-1 of Intermediate-57 by using5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoic acid (3.0g), conc.H₂SO₄ and sodium azide (0.793 g, 0.012 mmol) to afford 2.1 g ofthe desired product.

Step-2:—Preparation ofN-(4-chloro-2-fluoro-5-hydrazinylbenzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described instep-1 of Intermediate-61 by usingN-(5-amino-4-chloro-2-fluorobenzyl)-2,2,2-trifluoroacetamide (2.0 g,0.007 mmol), NaNO₂ (0.612 g, 0.008 mmol), SnCl₂.2H₂O (4.10 g, 0.018mmol), and conc. HCl (100 mL) to afford 1.0 g of the desired product.

Step-3:—Preparation of tert-butyl2-(2-chloro-4-fluoro-5-{[(trifluoroacetyl)amino]methyl}phenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by usingN-(4-chloro-2-fluoro-5-hydrazinylbenzyl)-2,2,2-trifluoroacetamide (1.00g, 3.5 mmol), BOC anhydride (1.14 g, 5.26 mmol), Na₂CO₃ (0.743 g, 7.01mmol), acetonitrile (20 mL) and water (10 mL) to afford 0.600 g of thedesired product.

Intermediate-90N-(4-Chloro-2-fluoro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

Step-1:—Preparation ofN-(4-chloro-2-fluoro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using 4-iodobenzoyl isocyanate (Intermediate-67, 0.700 g,1.8 mmol), tert-butyl2-(2-chloro-4-fluoro-5-{[(trifluoroacetyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-89, 0.992 g, 3.63 mmol), DCM (50 mL),trifluoro acetic acid (5.0 mL) to afford 0.600 g of the desired product.¹H NMR (300 MHz, DMSO d₆): δ 4.47 (s, 2H), 7.61 (d, J=2.1 Hz, 3H),7.86-7.90 (br d, 3H), 10.05 (br s, 1H).

Step-2:—Preparation of2-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-5-(4-iodophenyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-2-fluoro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide(0.550 g, 1.01 mmol), KOH (0.285 g, 5.09 mmol), water (5 mL) and THF(15.0 mL) to afford 0.400 g of the desired product. ¹H NMR (300 MHz,DMSO d₆): δ 3.59 (m, 2H), 3.71 (s, 1H), 7.38 (d, J=9.6 Hz, 1H), 7.54 (d,J=7.8 Hz, 1H), 7.60-7.69 (m, 4H).

Step-3:—Preparation ofN-(4-chloro-2-fluoro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described instep-2 of Intermediate-83 by using2-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-5-(4-iodophenyl)-2H-1,2,4-triazol-3(4H)-one(0.400 g, 0.900 mmol), pivaloyl chloride (0.2 mL, 1.35 mmol), DIPEA (2mL), and THF (10 mL) to afford 0.300 g of the desired product. ¹H NMR(300 MHz, DMSO d₆): δ 1.10 (s, 9H), 4.30 (d, J=5.4 Hz, 2H), 7.42-7.44(m, 1H), 7.62-7.66 (m, 3H), 7.88-7.91 (br d, 1H), 8.14 (m, 1H); MS(m/z): 529.42 (M⁺H)⁺.

Intermediate-915-(5-(Aminomethyl)-2-chlorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)-2H-1,2,4-triazol-3(4H)-one

Step-1:—PreparationN-(4-chloro-3-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoylisocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl2-[6-(trifluoromethyl)pyridin-3-yl]hydrazinecarboxylate(Intermediate-61, 0.431 g, 1.55 mmol), DCM (50 mL) and trifluoro aceticacid (5.0 mL) to afford 0.500 g of the desired product.

Step-2:—Preparation of5-(5-(aminomethyl)-2-chlorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-3-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(0.400 g), KOH (0.400 g), THF (5.0 mL), and water (5 mL) to afford 0.350g of the desired product.

Intermediate-925-(5-(Aminomethyl)-2-chlorophenyl)-2-(3-chloro-4-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one

Step-1:—Preparation ofN-(4-chloro-3-(1-(3-chloro-4-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoylisocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl2-(3-chloro-4-fluorophenyl)hydrazinecarboxylate (Intermediate-85, 0.455g, 1.55 mmol), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford0.200 g of the desired product.

Step-2:—Preparation of5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-chloro-4-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-3-(1-(3-chloro-4-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(0.300 g), KOH (0.300 g), water (5 mL) and THF (10.0 mL) to afford 0.150g of the desired product.

Intermediate-935-(5-(Aminomethyl)-2-chlorophenyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-triazol-3(4H)-one

Step-1:—Preparation ofN-(4-chloro-3-(1-(3-chloro-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoylisocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl2-(3-chloro-4-methylphenyl)hydrazinecarboxylate (Intermediate-87, 0.450g, 1.55 mmol), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford0.180 g of the desired product.

Step-2:—Preparation of5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-3-(1-(3-chloro-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(0.400 g), KOH (0.400 g), water (5 mL) and THF (10.0 mL) to afford 0.350g of the desired product.

Intermediate-94 tert-Butyl2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate

Step-1:—Preparation of N-(3-amino-4-chlorobenzyl)pivalamide

The title compound was prepared according to the procedure described instep-2 of Intermediate-83 by using 5-(aminomethyl)-2-chlorobenzenamine(2.0 g), pivaloyl chloride (0.2 mL), TEA (2 mL) and THF (10 mL) toafford 2.0 g of the desired product.

Step-2:—Preparation ofN-(4-chloro-3-hydrazinylbenzyl)-2,2-dimethylpropanamide

The title compound was prepared according to the procedure described instep-1 of Intermediate-61 by using N-(3-amino-4-chlorobenzyl)pivalamide(1.80 g), NaNO₂ (0.62 g, 0.009 mmol), SnCl₂.2H₂O (4.2 g, 0.018 mmol) andconc. HCl (30 mL) to afford 1.5 g of the desired product.

Step-3:—Preparation of tert-butyl2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by usingN-(4-chloro-3-hydrazinylbenzyl)-2,2-dimethylpropanamide (1.5 g, 0.005mmol), BOC anhydride (1.4 g, 0.006 mmol), Na₂CO₃ (0.922 g, 0.008 mmol),acetonitrile (30 mL) and water (5 mL) to afford 1.0 g of the desiredproduct.

Intermediate-95N-(4-Chloro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

To a solution of tert-butyl2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl hydrazinecarboxylate (Intermediate-94, 0.450 g, 1.55 mmol) in DCM (20 mL) wasadded solution of 4-iodobenzoyl isocyanate (Intermediate-67, 0.500 g,1.55 mmol) in DCM (10 mL) and the reaction mixture was stirred for 20 hat room temperature, followed by addition of trifluoro acetic acid (TFA,3 mL) and further stirred for 20 h at same temperature. The reactionmass was quenched in water, extracted with DCM and concentrated toafford crude product which was purified by column chromatography elutingwith MeOH:DCM to afford 0.180 g of the desired product.

Intermediate-965-(5-(Aminomethyl)-2-chlorophenyl)-2-(3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one

Step 1:—Preparation of tert-butyl2-[3-(trifluoromethyl)phenyl]hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using [3-(trifluoromethyl)phenyl]hydrazinehydrochloride (1.00 g, 0.0056 mol), BOC anhydride (1.4 g, 0.0067 mol),Na₂CO₃ (0.800 g, 0.008 mol), acetonitrile (10 mL) and water (2 mL) toafford 0.500 g of the desired product.

Step 2:—Preparation ofN-(4-chloro-3-(1-(3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoylisocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl2-[3-(trifluoromethyl)phenyl]hydrazinecarboxylate (0.428 g, 1.55 mmol),DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.400 g of thedesired product.

Step-3:—Preparation of5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared according to the procedure described inIntermediate-66 by usingN-(4-chloro-3-(1-(3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(0.400 g), KOH (0.200 g), water (2 mL) and THF (5.0 mL) to afford 0.200g of the desired product.

Intermediate-97 tert-Butyl2-(2-chloro-5-{[(2-methylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by usingN-(4-chloro-3-hydrazinylbenzyl)-2-methylpropanamide (2.5 g, 0.010 mol),BOC anhydride (2.5 g, 0.011 mol), Na₂CO₃ (1.6 g, 0.015 mol),acetonitrile (20 mL) and water (5 mL) to afford 1.500 g of the desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 1.03 (d, J=6.6 Hz, 6H), 1.41 (s,9H), 2.36-2.40 (m, 1H), 4.09 (d, J=6.3 Hz, 1H), 4.15 (d, J=5.4 Hz, 2H),7.18 (d, J=7.8 Hz, 2H), 7.32 (s, 1H), 8.24 (m, 2H); MS (m/z): 340.8(M−H)⁻.

Intermediate-98N-(4-Chloro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide

The title compound was prepared according to the procedure described inExample-83 by using 4-iodobenzoyl isocyanate (Intermediate-67, 1.500 g),tert-butyl2-(2-chloro-5-{[(2-methylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate(Intermediate-97, 1.0 g), DCM (20 mL), and trifluoro acetic acid (5.0mL) to afford 0.500 g of the desired product. ¹H NMR (400 MHz, DMSO d₆):δ 1.02 (d, J=6.9 Hz, 6H), 2.44 (m, 1H), 4.28 (d, J=8.7 Hz, 2H), 7.28 (brs, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.44 (s, 1H), 7.61 (d, J=8.7 Hz, 1H),7.91 (d, J=8.1 Hz, 2H), 8.38 (m, 1H), 12.61 (m, 1H); MS (m/z): 495.7(M−H)⁻.

Intermediate-99 3-Fluoro-4-(trifluoromethyl)benzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using 3-fluoro-4-(trifluoromethyl)benzamide(0.200 g), oxalyl chloride (0.025 mL) and EDC (15 mL) to afford 0.150 gof the desired product.

Intermediate-100 4-Chloro-3-(trifluoromethyl)benzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using 4-chloro-3-(trifluoromethyl)benzamide(0.200 g), oxalyl chloride (0.012 mL) and EDC (15 mL) to afford 0.150 gof the desired product.

Intermediate-101 4-Fluoro-3-(trifluoromethyl)benzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using 4-fluoro-3-(trifluoromethyl)benzamide(0.200 g), oxalyl chloride (0.012 mL) and EDC (15 mL) to afford 0.150 gof the desired product.

Intermediate-102 3-Fluoro-4-iodobenzoyl isocyanate

Step-1:—Preparation of 3-fluoro-4-iodobenzamide

To a solution of 3-fluoro-4-iodobenzonitrile (2.7 g, 0.010 mmol) in DMSO(6.0 mL), K₂CO₃ (0.450 g, 0.003 mmol) and 30% H₂O₂ (2.4 mL) were addedat 0-10° C. and the reaction mass was stirred at RT for 2 h. Aftercompletion of the reaction, the reaction mass was quenched in ice coldwater. The obtained solid product was filtered off to afford 2.0 g ofthe desired title product. ¹H NMR (400 MHz, DMSO d₆): δ 7.48-7.51 (m,2H), 7.66 (br s, 1H), 7.69-7.70 (m, 1H), 8.09 (brs, 1H).

Step-2:—Preparation of 3-fluoro-4-iodobenzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using 3-fluoro-4-iodobenzamide (2.0 g),oxalyl chloride (0.120 mL) and EDC (25 mL) to afford 1.0 g of thedesired product.

Intermediate-103N-(3-(3-(4-(bromomethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-4-chlorobenzyl)pivalamide

Step-1:—Preparation of 4-(bromomethyl)benzamide

Stirred the solution of 4-(bromomethyl)benzonitrile (1.5 g) incocn.H₂SO₄ at 100° C. for 3-4 h. After completion of the reaction, thereaction mass was quenched in ice and filtered to afford 0.900 ofdesired product. ¹H NMR (400 MHz, DMSO d6): δ 4.71 (s, 2H), 7.26 (br s,1H), 7.49 (d, J=7.8 Hz, 2H), 7.82 (d, J=7.8 Hz, 2H), 7.89 (br s, 1H); MS(m/z): 214.36 (M+H)⁺.

Step-2:—Preparation of 4-(bromomethyl)benzoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using 4-(bromomethyl)benzamide (0.200 g),oxalyl chloride (0.012 mL) and EDC (15 mL) to afford 0.150 g of thedesired product.

Step-3:—Preparation ofN-(3-(3-(4-(bromomethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-4-chlorobenzyl)pivalamide

The title compound was prepared according to the procedure described inExample-83 by using 4-(bromomethyl)benzoyl isocyanate (0.150 g),tert-Butyl2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate(Intermediate-94, 0.150 g), DCM (20 mL), and trifluoro acetic acid (5.0mL) to afford 0.100 g of the desired product. ¹H NMR (400 MHz, DMSO d₆):δ 1.12 (s, 9H), 4.28 (br d, 2H), 4.75 (s, 2H), 7.34 (br d, 2H), 7.43 (brs, 1H), 7.60 (br d, 2H), 7.81 (br d, 2H), 8.17 (br s, 1H), 12.57 (s,1H).

Intermediate-104 4-(5-isopropyl-1,3,4-oxadiazol-2-yl)benzoyl isocyanate

Step 1:—Preparation of 4-(5-isopropyl-1,3,4-oxadiazol-2-yl)benzamide

The title compound was prepared according to the procedure described instep1 of Intermediate-59 by using4-(5-isopropyl-1,3,4-oxadiazol-2-yl)benzonitrile (0.500 g, 2.34 mmol),50% H₂O₂ (5.0 mL), K₂CO₃ (0.097 g, 0.070 mmol) to afford 0.250 g ofdesired product. ¹H NMR (400 MHz, DMSO d6): δ 1.3 (s, 3H), 1.35 (s, 3H),3.33 (m, 1H), 7.56 (br s, 1H), 8.06 (s, 4H), 8.16 (br s, 1H); MS (m/z):232.30 (M+H)⁺.

Step 2:—Preparation of 4-(5-isopropyl-1,3,4-oxadiazol-2-yl)benzoylisocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using4-(5-isopropyl-1,3,4-oxadiazol-2-yl)benzamide (0.200 g), oxalyl chloride(0.012 mL) and EDC (15 mL) to afford 0.150 g of the desired product.

Intermediate-105 tert-Butyl2-(4-chloro-3-methylphenyl)hydrazinecarboxylate

Step-1:—Preparation of 1-(4-chloro-3-methylphenyl)hydrazine

The title compound was prepared according to the procedure described instep-1 of Intermediate-61 by using N-4-chloro-3-methylbenzenamine (2.0g, 0.014 mmol), NaNO₂ (01.16 g, 0.0169 mmol), SnCl₂.2H₂O (7.93 g, 0.0352mmol) and conc. HCl (30 mL) to afford 1.5 g of the desired product.

Step-2:—Preparation of tert-butyl2-(4-chloro-3-methylphenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by using 1-(4-chloro-3-methylphenyl)hydrazine(1.22 g, 0.011 mmol), BOC anhydride (2.0 g, 0.009 mmol), Na₂CO₃ (0.922g, 0.008 mmol), acetonitrile (30 mL) and water (5 mL) to afford 1.0 g ofthe desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.40 (s, 9H), 2.21 (s,3H), 6.49 (d, J=8.4 Hz, 1H), 6.58 (s, 1H), 7.13 (d, J=8.7 Hz, 1H), 7.65(s, 1H), 8.78 (s, 1H).

Intermediate-1065-(5-(aminomethyl)-2-chlorophenyl)-2-(4-chloro-3-methylphenyl)-2H-1,2,4-triazol-3(4H)-one

Step-1:—Preparation ofN-(4-chloro-3-(1-(4-chloro-3-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoylisocyanate (step-3 of Intermediate-26, 1.0 g, 0.003 mmol), tert-butyl2-(4-chloro-3-methylphenyl)hydrazinecarboxylate (Intermediate-105, 1.500g), DCM (20 mL), and trifluoro acetic acid (5.0 mL) to afford 0.600 g ofthe desired product. ¹H NMR (300 MHz, DMSO d₆): δ 2.38 (s, 3H), 4.45 (d,J=5.4 Hz, 2H), 7.53 (d, J=9.3 Hz, 2H), 7.67 (s, 2H), 7.82 (d, J=8.1 Hz,1H), 7.92 (s, 1H), 10.08 (t, 1H), 12.61 (s, 1H); MS (m/z): 445.31(M+H)⁺.

Step-2:—Preparation of3-(5-(aminomethyl)-2-chlorophenyl)-1-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one

The solution ofN-(4-chloro-3-(1-(4-chloro-3-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(0.550 g, 1.23 mmol) in 20% aq. KOH (20 mL) was stirred for 2-3 h at RT.Excess of solvent was removed under vacuum and filtered off remainingreaction mass to afford 0.400 g of desired product. MS (m/z): 349.34(M)⁺.

Intermediate-107 was prepared according to the procedure described forstep-2 of Intermediate-26 by using5-cyano-2-cyclopropylpyridine-3-carboxylic acid, oxalyl chloride,ammonia gas, DMF, THF and DCM.

No. & Chemical Structure Chemical name and Characterization dataIntermediate-107  

5-cyano-2-cyclopropylpyridine-3- carboxamide. ¹H NMR (300 MHz, DMSO d₆):δ 107 (m, 4H), 2.49 (s, 1H), 7.82 (s, 1H), 8.13 (s, 1H), 8.20 (s, 2H),8.87 (s, 1H); MS (m/z): 188.04 (M + H)⁺.

The Intermediate-108 to Intermediate-115 were prepared by following theprocedure described for step-1 of Intermediate-61 by using correspondingamine, NaNO₂, SnCl₂.H₂O, 4N HCl and followed by following the proceduredescribed for step-3 of Intermediate-7 using BOC anhydride, Na₂CO₃ inacetonitrile and water.

No. Structure Chemical name and Characterization data Intermediate- 108

tert-butyl 2-(4-iodophenyl)hydrazinecarboxylate. MS (m/z): 335.15 (M +H)⁺. Intermediate- 109

tert-butyl 2-[3-fluoro-4- (trifluoromethyl)phenyl]hydrazinecarboxylate.MS (m/z): 295.21 (M + H)⁺. Intermediate- 110

ten-butyl 2-[3-fluoro-5- (trifluoromethyl)phenyl]hydrazinecarboxylate.MS (m/z): 295.24 (M + H)⁺. Intermediate- 111

tert-butyl 2-[4-chloro-3- (trifluoromethyl)phenyl]hydrazinecarboxylate.¹H NMR (300 MHz, DMSO d₆): δ 1.40 (s, 9H), 6.90 (d, J = 8.7 Hz, 1H),7.01 (s, 1H), 7.45 (d, J = 9.0 Hz, 1H), 8.20 (s, 1H), 8.99 (br s, 1H.Intermediate- 112

tert-butyl 2-[4-methyl-3- (trifluoromethyl)phenyl]hydrazinecarboxylate.¹H NMR (300 MHz, DMSO d₆): δ 1.40 (s, 9H), 2.28 (s, 3H), 6.80 (d, J =8.4 Hz, 1H), 6.91 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 8.88(br s, 1H). Intermediate- 113

tert-butyl 2-[2-methyl-4- (trifluoromethyl)phenyl]hydrazinecarboxylate.MS (m/z): 291.12 (M + H)⁺. Intermediate- 114

tert-butyl 2-[2-fluoro-4- (trifluoromethyl)phenyl]hydrazinecarboxylate¹H NMR (300 MHz, DMSO d₆): δ 1.42 (s, 9H), 6.83 (t, 1H), 7.39 (d, J =8.4 Hz, 1H), 7.44-7.48 (m, 1H), 8.28 (s, 1H), 9.03 (s, 1H).Intermediate- 115

tert-butyl 2-(3-fluoro-4- iodophenyl)hydrazinecarboxylate. MS (m/z):351.14 (M − H)⁻.

The Intermediate-116 to Intermediate-128 was prepared by following theprocedure described for Example-83 by using corresponding startingmaterial mentioned in the table below, DCM and TFA.

Starting Intermediate No. and Intermediate chemical name andcharacterization material used Structure data Intermediate- 65 +Intermediate- 67 Intermediate-116  

N-(3-(4,5-dihydro-1-(4-iodophenyl)-5-oxo-1H-1,2,4-triazol-3-yl)-2.4-dimethylbenzyl)-2,2,2- trifluoroacetamide. ¹HNMR (300 MHz, DMSO d₆): δ 2.19 (s, 3H), 2.21 (s, 3H), 4.41 (d, J = 4.8Hz, 2H), 7.20 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.53-7.82(m, 4H), 9.97 (s, 1H), 12.23 (s, 1H); MS (m/z): 517.301 (M + H)⁺. Step 3product of Intermediate- 26 + Intermediate- 110 Intermediate-117  

N-(4-chloro-3-(1-(3-fluoro-5-(trifiuoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide. ¹H NMR (300 MHz,DMSO d₆): δ 4.46 (d, 2H), 7.51 (m, 1H), 7.60 (d, J = 9.3 Hz, 1H),7.66-7.69 (m, 2H), 8.08 (d, J = 13.8 Hz, 1H), 8.16 (s, 1H), 10.09 (m,1H), 12.84 (m, 1H) Step-3 product of Intermediate- 26 + Intermediate-111 Intermediate-118  

N-(4-chloro-3-(1-(4-chloro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide. ¹H NMR (300 MHz,DMSO d₆): δ 4.46 (d, J = 6.0 Hz, 2H), 7.49 (d, J = 10.2 Hz, 1H), 7.67(d, J = 8.4 Hz, 2H), 7.85 (d, J = 9.0 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H),8.44 (s, 1H), 10.09 (t, 1H), 12.80 (s, 1H); MS (m/z): 499.31 (M + H)⁺.Intermediate- 94 + Intermediate- 102 Intermediate-119  

N-(4-chloro-3-(3-(3-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1- yl)benzyl)pivalamide. ¹H NMR (300 MHz,DMSO d₆): δ 1.12 (s, 9H), 4.28 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 7.8 Hz,1H), 7.43-7.49 (m, 2H), 7.59-7.67 (m, 2H), 8.02 (t, J = 7.2 Hz, 1H),8.19 (t, 1H), 12.67 (s, 1H); MS (m/z): 529.05 (M + H)⁺. Step-3 productof Intermediate- 26 + Intermediate- 67 Intermediate-120  

N-(4-chloro-3-(4,5-dihydro-1-(4-iodophenyl)-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2- trifluoroacetamide. ¹H NMR (300MHz, DMSO d₆): δ 4.44 (br s, 2H), 7.46-7.73 (m, 4H), 7.80 (s, 2H), 10.11(s, 1H); MS (m/z): 523.09 (M + H)⁺. Step-3 product of Intermediate- 26 +Intermediate- 112 Intermediate-121  

N-(4-chloro-3-(1-(3-(trifluoromethyl)-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-(riazol-3-yl)benzyl)-2,2,2-trifluoroacetamide. ¹H NMR (300 MHz, DMSO d₆): δ 2.45(s, 3H), 4.46 (d, J = 6.6 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.57 (d, J= 7.8 Hz, 1H), 7.68 (s, 2H), 8.10 (d, J = 8.7 Hz, 1H), 8.28 (s, 1H),10.09 (br s, 1H), 12.69 (br s, 1H); MS (m/z): 476.91 (M − H)⁻.Intermediate- 53 +  

Intermediate-122  

6-cyclopropyl-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridine-3- carbonitrile. ¹H NMR(300 MHz, DMSO d₆): δ 1.18 (m, 2H), 1.39 (m, 2H), 3.01 (m, 1H), 7.85 (d,J = 9.0 Hz, 2H), 8.20 (d, J = 7.8 Hz, 2H), 8.45 (s, 1H), 8.99 (s, 1H),12.82 (br s, 1H); MS (m/z): 372.24 (M + H)⁺. Step-3 product ofIntermediate- 26 + Intermediate- 113 Intermediate-123  

N-(4-chloro-3-(1-(4-(trifluoromethyl)-2-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide. ¹H NMR (300 MHz, DMSO d₆): δ 2.39(s, 3H), 4.44 (br d, 2H), 7.33-7.90 (m, 6H), 10.07 (br s, 1H), 12.51 (s,1H): MS (m/z): 479.10 (M + H)⁺. Intermediate- 47 + Intermediate- 94Intermediate-124  

N-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1- yl)benzyl)pivalamide. ¹H NMR (300 MHz,DMSO d₆): δ 1.11 (s, 9H), 4.28 (d, J = 5.7 Hz, 2H), 7.34 (d, J = 8.4 Hz,1H), 7.42 (s, 1H), 7.53-7.61 (m, 2H), 7.75 (d, J = 7.2 Hz, 1H), 7.89 (d,J = 9.3 Hz, IH), 8.18 (t, 1H), 12.43 (s, 1H); MS (m/z): 529.0110 (M +H)⁺. Step-3 product of Intermediate- 26 + Intermediate- 109Intermediate-125  

N-(4-chloro-3-(1-(3-fluoro-4-(trifiuoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide. ¹H NMR (300 MHz,DMSO d₆): δ 4.46 (d, J = 6.0 Hz, 2H), 7.50 (d, J = 8.7 Hz, 1H), 7.66 (s,2H), 7.92-8.07 (m, 3H), 10.10 (t, 1H), 12.84 (m, 1H). Step-3 product ofIntermediate- 26 +  

Intermediate-126  

N-(4-chloro-3-(1-(2-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2- trifluoroacetamide.¹H NMR (300 MHz, DMSO d₆): δ 4.44 (d, J = 5.1 Hz, 2H), 7.39-7.48 (m,2H), 7.63 (br s, 2H), 7.74 (t, J = 8.4 Hz, 1H), 7.90 (d, J = 8.7 Hz,1H), 10.08 (br s, 1H), 12.52 (s, 1H); MS (m/z): 540.98 (M + H)⁺. Step-3product of Intermediate- 26 + Intermediate- 114 Intermediate-127  

N-(4-chloro-3-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide. ¹H NMR (300 MHz,DMSO d₆): δ 4.44 (m, 2H), 7.34 (s, 1H), 7.49 (m, 2H), 7.75 (d, J = 7.8Hz, 1H), 7.79-7.98 (m, 2H), 10.10 (br s, 1H), 12.64 (m, 1H); MS (m/z):483.12 (M + H)⁺ Intermediate- 65 + Intermediate- 115 Intermediate-128  

N-(3-(1-(3-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)-2,2,2-trifluoroacetamide. MS (m/z): 535.01 (M + H)⁺.

The Intermediate-129 to Intermediate-137 were prepared by following theprocedure described in step-2 of Intermediate-106 by using correspondingstarting material mentioned in the table below, KOH and water.

Starting Intermediate No. and Intermediate chemical name andcharacterization material used Structure data Intermediate- 116Intermediate-129  

5-(3-(aminomethyl)-2,6-dimethylphenyl)-2-(4-iodophenyl)-2H-1,2,4-triazol-3(4H)-one. ¹H NMR (300 MHz, DMSO d₆): δ2.10 (s, 3H), 2.12 (s, 3H), 3.13 (br s, 2H), 3.66 (s, 2H), 6.98 (d, J =8.4 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.90(d, J = 8.7 Hz, 2H). Intermediate- 117 Intermediate-130  

5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one Intermediate- 118Intermediate-131  

5-(5-(aminomethyl)-2-chlorophenyl)-2-(4-chloro-3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one Intermediate- 120Intermediate-132  

5-(5-(aminomethyl)-2-chlorophenyl)-2-(4-iodophenyl)-2H-1,2,4-triazol-3(4H)-one. ¹H NMR (300 MHz, DMSO d₆): δ3.36 (br s, 2H), 3.80 (br s, 2H), 7.41 (m, 1H), 7.47 (m, 1H), 7.6-7.72(m, 2H), 7.77 (s, 1H), 7.87-7.90 (m, 2H). Intermediate- 121Intermediate-133  

5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-(trifluoromethyl)-4-methylphenyl)-2H-1,2,4-triazol- 3(4H)-one. MS (m/z):381.01 (M − H)⁻. Intermediate- 123 Intermediate-134  

5-(5-(aminomethyl)-2-chlorophenyl)-2-(4-(trifluoromethyl)-2-methylphenyl)-2H-1,2,4-triazol- 3(4H)-one. MS (m/z):383.15 (M + H)⁺. Intermediate- 125 Intermediate-135  

5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)- one. MS (m/z): 387.21(M + H)⁺. Intermediate- 127 Intermediate-136  

5-(5-(aminomethyl)-2-chlorophenyl)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)- one. MS (m/z): 387.06(M + H)⁺. Intermediate- 128 Intermediate-137  

5-(3-(aminomethyl)-2,6-dimethylphenyl)-2-(3-fluoro-4-iodophenyl)-2H-1,2,4-triazol-3(4H)-one. MS (m/z): 439.24 (M +H)⁺.

The Intermediate-138 to Intermediate-141 were prepared by following theprocedure described in Example-108 by using corresponding startingmaterial mentioned in the table below, TEA and THF.

Starting Intermediate No. and Intermediate chemical name andcharacterization material used Structure data Intermediate- 129 +Pivaloyl chloride Intermediate-138  

N-(3-(4,5-dihydro-1-(4-iodophenyl)-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)pivalamide. ¹H NMR (300 MHz, DMSOd₆): δ 1.19 (s, 9H), 2.15 (s, 3H), 2.19 (s, 3H), 4.22 (d, 2H), 7.17-7.21(m, 2H), 7.79 (m, 4H), 8.00 (m, 1H), 12.00 (s, 1H). Intermediate- 132 +Pivaloyl chloride Intermediate-139  

N-(4-chloro-3-(4,5-dihydro-1-(4-iodophenyl)-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide. ¹H NMR (300 MHz, DMSO d₆): δ1.13 (s, 9H), 4.29 (d, J = 5.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.59(s, 2H), 7.80 (q, J = 6.3 Hz, 4H), 8.19 (m, 1H), 12.59 (s, 1H); MS(m/z): 511.16 (M + H)⁺. Intermediate- 129 + Isopropyl chlorideIntermediate-140  

N-(3-(4,5-dihydro-1-(4-iodophenyl)-5-oxo-1H- 1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)isobutyramide. ¹H NMR (300 MHz, DMSO d₆): δ 1.23 (s, 3H),1.35 (s, 3H), 2.06 (s, 3H), 2.20 (s, 3H), 4.23 (br s, 2H), 7.08 (d, J =7.8 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.85(d, J = 8.1 Hz, 2H), 8.17 (t, 1H). Intermediate- 137 + Isopropylchloride Intermediate-141  

N-(3-(1-(3-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4- dimethylbenzyl)isobutyramide. MS (m/z):509.02 (M + H)⁺.

The Intermediate-142 was prepared by following the procedure describedin Example-107 by using Intermediate-129, THF, DMF,3-methoxy-2,2-dimethylpropanoic acid, TBTU and TEA.

Starting Intermediate No. and Intermediate chemical name andcharacterization material used Structure data Intermediate- 129Intermediate-142  

N-(3-(4,5-dihydro-1-(4-iodophenyl)-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)-3-hydroxy-2,2-dimethylpropanamide. ¹H NMR (300 MHz, DMSO d₆): δ 1.08 (m, 6H), 2.15(s, 3H), 2.19 (s, 3H), 3.41 (m, 2H), 4.25 (d, 2H), 4.92 (m, 1H), 6.93(d, J = 6.9 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H),7.79 (s, 3H), 7.92 (t, 1H), 12.25 (s, 1H); MS (m/z): 521.18 (M + H)⁺.

The Intermediate-143 was prepared by following the procedure describedin step-2 of Example-134 by using Intermediate-142, DAST and THF.

Starting Intermediate No. and Intermediate chemical name andcharacterization material used Structure data Intermediate- 142Intermediate-143  

N-(3-(4,5-dihydro-1-(4-iodophenyl)-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)-3-fluoro-2,2-dimethylpropanamide. ¹H NMR (300 MHz, DMSO d₆): δ 1.08 (m, 6H), 2.15(s, 3H), 2.19 (s, 3H), 3.34 (m, 2H), 4.25 (d, 2H), 6.91 (m, 1H), 7.15(m, 1H), 7.25-7.27 (m, 1H), 7.79 (s, 3H), 8.08 (s, 1H), 12.24 (s, 1H);MS (m/z): 521.03 (M + H)⁺.

Intermediate-144N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2-methylpropane-2-sulfinamide

The title compound was prepared according to the procedure described inExample-108 by using3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-63, 0.450 g, 1.22 mmol), 2-methylpropane-2-sulfinicchloride (0.205 g, 1.46 mmol), TEA (2.0 mL), DCM (10 mL) to afford 0.250g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.23 (s, 9H),4.24 (m, 2H), 7.63-7.87 (m, 4H), 7.86 (d, J=8.7 Hz, 2H), 8.19 (d, J=9.0Hz, 2H); MS (m/z): 472.095 (M+H)⁺.

Intermediate-145 5-Cyano-2-(difluoromethyl)nicotinoyl isocyanate

Step-1:—Preparation of ethyl 5-cyano-2-(difluoromethyl)nicotinate

The title compound was prepared according to the procedure described instep-2 of Example-134 by using ethyl 5-cyano-2-formylnicotinate (6.0 g,0.029 mmol), DAST (11.8 mL, 0.088 mmol), DCM (200 mL) to afford 3.5 g ofdesired product. MS (m/z): 227.06 (M+H)⁺.

Step-2:—Preparation of 5-cyano-2-(difluoromethyl)nicotinic acid

To a solution of ethyl 5-cyano-2-(difluoromethyl)nicotinate (1.2 g, 5.3mmol) in THF: water (20 mL: 5 mL) was added LiOH.H₂O (0.267 g, 6.3 mmol)at 0° C. and the reaction mass was stirred for 40-60 minutes. Thereaction mass was acidified with dil. HCl and extracted with ethylacetate. The organic layer was separated, dried over anhydrous sodiumsulphate and concentrated to afford 0.700 g of the desired product. ¹HNMR (300 MHz, DMSO d₆): δ 7.37-7.72 (t, J=53.7 Hz, 1H), 8.24 (s, 1H),9.30 (s, 1H), 14.25 (br s, 1H); MS (m/z): 199.34 (M+H)⁺.

Step-3:—Preparation of 5-cyano-2-(difluoromethyl)nicotinamide

To a solution of 5-cyano-2-(difluoromethyl)nicotinic acid (0.600 g, 3.0mmol) in dry DMF (20 mL), TBTU (10.0 g, 3.33 mmol) was added at 0° C.followed by slow addition of DIPEA (0.7 mL, 3.93 mmol). The reactionmass was stirred at 0° C. for 1 h and ammonium chloride (3.33 g, 60.7mmol) was added. The reaction mass was stirred at RT for 30-48 h. Aftercompletion of reaction quenched the reaction mass with DCM, filtered offsolid to afford 0.500 g of the desired product. ¹H NMR (300 MHz, DMSOd₆): δ 8.16 (m, 1H), 8.63 (s, 1H), 9.22 (s, 1H).

Step-4:—Preparation of 5-cyano-2-(difluoromethyl)nicotinoyl isocyanate

The title compound was prepared according to the procedure described instep-2 of Intermediate-8 by using 5-cyano-2-(difluoromethyl)nicotinamide(1.0 g), oxalyl chloride (3.2 g, 25.3 mmol) and DCM (20 mL) to afford1.0 g of the desired product.

Intermediate-146N-(4-Chloro-3-(3-(4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide

Step-1:—PreparationN-(4-chloro-3-hydrazinylbenzyl)-2,2,2-trifluoroacetamide

To a cold solution ofN-(3-amino-4-chlorobenzyl)-2,2,2-trifluoroacetamide (0.500 g, 0.017mmol) in 6N HCl (50.0 mL), aqueous solution of NaNO₂ (1.29 g, 0.018mmol) was added at 0° C. and the reaction mass was stirred at 0-5° C.for 30 min. The reaction mass was added to a solution of SnCl₂.H₂O(22.18 g, 0.98 mmol) in 6N HCl at 0-5° C. and further continued stirringfor 5-6 h at same temperature. The reaction mass was cooled, basifiedand extracted with DCM. The organic layer was separated, dried andconcentrated to afford 0.700 g of the desired product. ¹H NMR (300 MHz,DMSO d₆): δ 4.22 (br s, 2H), 4.29 (d, J=6.0 Hz, 2H), 6.42-6.67 (m, 2H),7.14-7.16 (m, 2H), 9.98 (br s, 1H).

Step-2:—Preparation tert-butyl2-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)hydrazinecarboxylate

The title compound was prepared according to the procedure described instep-3 of Intermediate-7 by usingN-(4-chloro-3-hydrazinylbenzyl)-2,2,2-trifluoroacetamide (0.350 g, 1.3mmol), BOC anhydride (0.316 g, 1.4 mmol), Na₂CO₃ (1.19 g, 1.9 mmol),acetonitrile (20 mL) and water (10 mL) to afford 0.500 g of desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 1.41 (s, 9H), 4.28 (d, J=5.7 Hz,2H), 6.61-6.65 (m, 2H), 7.22 (d, J=8.1 Hz, 1H), 7.41 (s, 1H), 9.91 (s,1H), 9.97 (s, 1H).

Step-3:—Preparation ofN-(4-chloro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide

The title compound was prepared according to the procedure described inExample-83 by using 4-iodobenzoyl isocyanate (Intermediate-67, 1.500 g),tert-butyl2-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)hydrazinecarboxylate(1.0 g), DCM (20 mL), and trifluoro acetic acid (5.0 mL) to afford 0.500g of the desired product. ¹H NMR (400 MHz, DMSO d₆): δ 4.44 (d, J=6.0Hz, 2H), 7.41 (d, J=7.8 Hz, 1H), 7.52 (s, 1H), 7.60-7.67 (m, 2H), 7.81(d, J=8.4 Hz, 1H), 7.90 (d, J=8.7 Hz, 2H), 10.09 (br s, 1H), 12.63 (s,1H).

EXAMPLES Example-12-(4-Bromophenyl)-4-(2-chloro-6-fluorophenyl)-2,5-dihydro-1,2,3,5-thiatriazole-1-oxide

The title compound was prepared according to the procedure described instep-4 of Intermediate-1 usingN′-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbohydrazonamide (step-3 ofIntermediate-1, 0.100 g, 0.292 mmol), CHCl₃ (10 mL), pyridine (2.0 mL)and thionyl chloride (1.0 mL). The obtained product was purified withcolumn chromatography on silica gel eluting with 0.5% MeOH:DCM to afford0.050 g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.45 (t,J=6.9 Hz, 3H), 7.51-7.68 (m, 4H), 12.05 (br s, 1H); MS (m/z): 388.02(M)⁻.

Example-25-(2-Chloro-6-fluorophenyl)-2-{4-[6-(trifluoromethyl)pyridin-3-yl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

To a solution of2-(4-bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate-1, 0.100 g, 0.271 mmol) in DMSO (3.0 mL) was added[6-(trifluoromethyl)pyridin-3-yl]boronic acid (0.078 g, 0.40 mmol),K₂CO₃(0.112 g, 0.81 mmol) and tetrakistriphenyl phosphine palladium (0)(0.062 g, 0.054 mmol). The reaction mass was stirred at 110° C. for24-48 h. The reaction mass was quenched in water and extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulphate and concentrated. The obtained product was purified with columnchromatography on silica gel eluting with 4-5% EA:DCM to afford 0.030 gof the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.38-7.48 (m, 1H),7.61-7.63 (m, 1H), 7.88-7.99 (m, 4H), 8.01-8.17 (m, 2H), 8.41 (d, J=7.8Hz, 1H), 9.14 (s, 1H), 12.60 (br s, 1H). MS (m/z): 435.25 (M+H)⁺.

Example-35-(2-Chloro-6-fluorophenyl)-2-(4-{[2-(trifluoromethyl)phenyl]ethynyl}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

To a solution of5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate-2, 0.100 g, 0.319 mmol) in DMSO was added1-iodo-2-(trifluoromethyl)benzene (0.13 g, 0.479 mmol), TBAF (0.301 g,0.958 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.050 g,0.071 mmol). The reaction mass was stirred at 110° C. for 5-6 h. Thereaction mass was quenched in water and extracted with DCM andconcentrated. The obtained product was purified with columnchromatography on silica gel eluting with 2.0% EA:DCM to afford 0.040 gof the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.50 (t, J=9.3 Hz,1H), 7.57-7.73 (m, 6H), 7.82 (br s, 2H), 8.02 (d, J=8.7 Hz, 2H), 12.72(br s, 1H). MS (m/z): 458.26 (M+H)⁺.

Example-45-[2-Fluoro-6-(4-methylthiophen-2-yl)phenyl]-2-[4-(4-methylthiophen-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

The title compound was prepared according to the procedure described inExample-2 using2-(4-bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate-1, 0.100 g, 0.271 mmol), (4-methylthiophen-2-yl)boronicacid (0.059 g, 0.407 mmol), K₂CO₃ (0.112 g, 0.81 mmol),tetrakistriphenyl phosphine palladium (0) (0.062 g, 0.054 mmol) and DMSO(3.0 mL) to afford 0.020 g of desired product. ¹H NMR (300 MHz, CDCl₃):δ 2.29 (s, 6H), 6.86 (s, 1H), 6.91 (s, 2H), 7.13 (s, 1H), 7.21 (d, J=9.3Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.48-7.55 (m, 1H), 7.61 (d, J=8.1 Hz,2H), 7.92 (d, J=9.0 Hz, 2H), 9.27 (br s, 1H). MS (m/z): 384.88 (M−H)⁻.

Example-55-(2-Chloro-6-fluorophenyl)-2-{4-[(6-fluoropyridin-3-yl)ethynyl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

The title compound was prepared according to the procedure described inExample-3 using5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate-2, 0.100 g, 0.319 mmol), 2-fluoro-5-iodopyridine (0.106 g,0.479 mmol), TBAF (0.201 g, 0.638 mmol),bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) andDMSO (3.0 mL). The obtained product was purified with columnchromatography on silica gel eluting with 2.0% MeOH:DCM to afford 0.030g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.30 (d, J=7.5Hz, 1H), 7.51 (t, J=8.7 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.1Hz, 3H), 8.03 (d, J=8.4 Hz, 2H), 8.20 (t, J=7.2 Hz, 1H), 8.49 (s, 1H),12.73 (br s, 1H). MS (m/z): 407.33 (M−H)⁻.

Example-65-(2-Chloro-6-fluorophenyl)-2-{4-[(4-chloro-2-fluorophenyl)ethynyl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

The title compound was prepared according to the procedure described inExample-3 using5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate-2, 0.100 g, 0.319 mmol), 4-chloro-2-fluoro-1-iodobenzene(0.123 g, 0.479 mmol), TBAF (0.201 g, 0.638 mmol),bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) andDMSO (3.0 ml). The obtained crude product was purified with columnchromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.045g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.38 (d, J=8.4Hz, 1H), 7.50 (t, J=8.7 Hz, 1H), 7.57-7.70 (m, 6H), 8.02 (d, J=8.7 Hz,2H), 12.74 (br s, 1H). MS (m/z): 442.38 (M+).

Example-75-(2-Chloro-6-fluorophenyl)-2-(4-{[2-chloro-4-(trifluoromethyl)phenyl]ethynyl}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

The title compound was prepared according to the procedure described inExample-3 using5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate-2, 0.100 g, 0.319 mmol),2-chloro-1-iodo-4-(trifluoromethyl)benzene (0.147 g, 0.479 mmol), TBAF(0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride(0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product waspurified with column chromatography on silica gel eluting with 1.0%MeOH:DCM to afford 0.040 g of the desired product. ¹H NMR (300 MHz, DMSOd₆): δ 7.51 (d, J=8.7 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.67-7.87 (m,3H), 7.84 (t, J=8.4 Hz, 2H), 8.05 (d, J=8.4 Hz, 2H), 8.11 (s, 1H), 12.75(br s, 1H). MS (m/z): 492.22 (M+).

Example-85-(2-Chloro-6-fluorophenyl)-2-[3′-(trifluoromethoxy)biphenyl-4-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one

The title compound was prepared according to the procedure described inExample-2 using5-(2-chloro-6-fluorophenyl)-2-(4-iodophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(step-4 of Intermediate-2, 0.100 g, 0.242 mmol),[3-(trifluoromethoxy)phenyl]boronic acid (0.075 g, 0.363 mmol), K₂CO₃(0.100 g, 0.726 mmol), tetrakistriphenyl phosphine palladium (0) (0.055g, 0.048 mmol) and DMSO (3.0 mL) to afford 0.025 g of desired product.¹H NMR (300 MHz, CDCl₃): δ 7.19 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.39(d, J=7.8 Hz, 1H), 7.46 (d, J=6.6 Hz, 1H), 7.53 (t, J=7.8 Hz, 2H), 7.65(d, J=8.4 Hz, 2H), 8.12 (d, J=8.4 Hz, 2H), 10.01 (br s, 1H).

Example-95-(2-Chloro-6-fluorophenyl)-2-(4-{[3-(trifluoromethyl)phenyl]amino}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

To a solution of5-(2-chloro-6-fluorophenyl)-2-(4-iodophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(step-4 of Intermediate-2, 0.100 g, 0.242 mmol) in toluene (5.0 mL) wasadded 3-(trifluoromethyl)aniline (0.076 g, 0.292 mmol), NaOtBu (0.035 g,0.360 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.022 g, 0.024mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.021 g,0.036 mmol). The reaction mixture was refluxed for 12 h. The reactionmass was quenched in water and extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulphate and concentrated.

The obtained product was purified with column chromatography on silicagel eluting with 10% EA:DCM to afford 0.030 g of the desired product. ¹HNMR (300 MHz, DMSO d₆): δ 7.09 (d, J=7.5 Hz, 1H), 7.20 (s, 1H), 7.24 (d,J=5.7 Hz, 2H), 7.31 (d, J=8.1 Hz, 1H), 7.41-7.59 (m, 3H), 7.69 (d, J=7.8Hz, 1H), 7.81 (d, J=8.7 Hz, 2H), 8.64 (s, 1H), 12.51 (s, 1H). MS (m/z):449.31 (M+H)⁺.

Example-105-(2-Chloro-6-fluorophenyl)-2-{4-[(2,5-dichlorophenyl)ethynyl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

The title compound was prepared according to the procedure described inExample-3 using5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate-2, 0.100 g, 0.319 mmol), 1,4-dichloro-2-iodobenzene (0.130g, 0.470 mmol), TBAF (0.201 g, 0.638 mmol),bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) andDMSO (3.0 mL). The obtained product was purified with columnchromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.040g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.50-7.72 (m,7H), 7.82 (s, 1H), 8.05 (d, J=8.7 Hz, 2H), 12.75 (br s, 1H). MS (m/z):458.31 (M+).

Example-111-(4-Bromophenyl)-3-(2-chloro-6-fluorophenyl)-N-(3-methoxypropyl)-1H-1,2,4-triazol-5-amine

To a solution of1-(4-bromophenyl)-5-chloro-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazole(Intermediate-3, 0.100 g, 0.257 mmol) in DMF (3.0 mL) was added3-methoxypropan-1-amine (0.035 g, 0.386 mmol) and DIPEA (1.0 mL). Thereaction mass was stirred at 80° C. for 5-6 h. The reaction mass wasquenched in water and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulphate and concentrated to afford0.040 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.92 (d, J=5.4Hz, 2H), 2.34 (t, J=7.5 Hz, 2H), 3.28 (s, 3H), 3.56-3.64 (m, 2H), 5.69(m, 1H), 7.06-7.15 (m, 1H), 7.22-7.49 (m, 2H), 7.54 (d, J=10.2 Hz, 2H),7.64 (d, J=8.4 Hz, 2H). MS (m/z): 441.19 (M+H)⁺.

Example-121-(4-((3-Chloro-2-fluorophenyl)ethynyl)phenyl)-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared according to the procedure described inExample-3 using5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate-2, 0.100 g, 0.319 mmol), 1-chloro-2-fluoro-3-iodobenzene(0.123 g, 0.470 mmol), TBAF (0.201 g, 0.638 mmol),bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) andDMSO (3.0 mL). The obtained product was purified with columnchromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.040g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.29 (t, J=7.8Hz, 1H), 7.50 (t, J=8.7 Hz, 1H), 7.57-7.72 (m, 6H), 8.04 (d, J=9.0 Hz,2H), 12.74 (br s, 1H). MS (m/z): 442.35 (M+).

Example-135-(2-Chloro-6-fluorophenyl)-2-(4-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

The title compound was prepared according to the procedure described inExample-3 using5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate-2, 0.100 g, 0.319 mmol),2-bromo-5-(trifluoromethyl)pyridine (0.108 g, 0.479 mmol), TBAF (0.201g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g,0.028 mmol) and DMSO (3.0 mL). The obtained product was purified withcolumn chromatography on silica gel eluting with 1.0% MeOH:DCM to afford0.030 g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.51 (t,J=8.7 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.70 (t, J=6.3 Hz, 1H), 7.79 (d,J=8.7 Hz, 2H), 7.89 (d, J=8.1 Hz, 1H), 8.06 (d, J=8.4 Hz, 2H), 8.29 (d,J=7.8 Hz, 1H), 9.00 (s, 1H), 12.75 (br s, 1H). MS (m/z): 459.37 (M+).

Example-145-(2-Chloro-6-fluorophenyl)-2-{4-[(3-chloropyridin-4-yl)ethynyl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

The title compound was prepared according to the procedure described inExample-3 using5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate-2, 0.100 g, 0.319 mmol), 3-chloro-4-iodopyridine(Intermediate-4, 0.114 g, 0.429 mmol), TBAF (0.201 g, 0.638 mmol),bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) andDMSO (3.0 mL). The obtained product was purified with columnchromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.035g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 7.49 (t, J=8.7Hz, 1H), 7.56 (d, J=11.7 Hz, 2H), 7.60-7.77 (m, 3H), 8.08 (d, J=8.4 Hz,2H), 8.57 (d, J=5.1 Hz, 1H), 8.78 (s, 1H), 12.76 (br s, 1H). MS (m/z):425.43 (M⁺).

Example-153-(2-Chloro-6-fluorophenyl)-1-(4-((2-morpholinopyrimidin-5-yl)ethynyl)phenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared according to the procedure described inExample-3 using5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate-2, 0.100 g, 0.319 mmol),4-(5-iodopyrimidin-2-yl)morpholine (Intermediate-5, 0.139 g, 0.470mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II)chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained productwas purified with column chromatography on silica gel eluting with 2.0%MeOH:DCM to afford 0.035 g of the desired product. ¹H NMR (300 MHz, DMSOd₆): δ 3.67 (br s, 4H), 3.76 (br s, 4H), 7.47-7.71 (m, 5H), 7.98 (d,J=9.0 Hz, 2H), 8.58 (s, 2H), 12.69 (s, 1H).

Example-165-(2-Chloro-6-fluorophenyl)-2-(4-{[6-(morpholin-4-yl)pyridin-3-yl]ethynyl}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

The title compound was prepared according to the procedure described inExample-3 using5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Intermediate-2, 0.100 g, 0.319 mmol), 4-(5-iodopyridin-2-yl)morpholine(Intermediate-6, 0.139 g, 0.470 mmol), TBAF (0.201 g, 0.638 mmol),bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) andDMSO (3.0 mL). The obtained product was purified with columnchromatography on silica gel eluting with 2.0% MeOH:DCM to afford 0.020g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.58-3.61 (m,4H), 3.82-3.85 (br s, 4H), 6.64 (d, J=8.7 Hz, 1H), 7.19 (t, J=8.7 Hz,1H), 7.36-7.47 (m, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.63-7.67 (m, 1H), 8.03(d, J=9.0 Hz, 2H), 8.38 (s, 1H), 10.14 (br s, 1H); MS (m/z): 473.64(M−H)⁻.

Example-174-[3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-Nyclopropylmethyl)benzamide

To a solution of4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoicacid (Intermediate-9, 0.100 g, 0.290 mmol) in THF was added di-isopropylethyl amine (1.0 mL) and TBTU (0.193 g, 0.590 mmol). The reaction masswas stirred at RT for 1 h. 1-cyclopropylmethanamine (0.048 g, 0.440mmol) was added to the reaction mass and further stirred at RT for 15 h.The reaction mass was quenched in water and extracted with ethylacetate. The organic layer was washed with NaHCO₃ solution and water,dried over anhydrous sodium sulphate and concentrated to afford 0.025 gof desired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.23 (br s, 1H), 0.44(d, J=7.5 Hz, 1H), 0.83-0.85 (m, 1H), 1.06-1.024 (m, 1H), 1.31 (m, 1H),3.14 (t, J=5.7 Hz, 2H), 7.50 (t, J=9.0 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H),7.67-7.72 (m, 1H), 7.95-8.00 (m, 4H), 8.59 (m, 1H), 12.70 (br s, 1H); MS(m/z): 387.35 (M+H)⁺.

Example-184-[3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[2-(trifluoromethyl)benzyl]benzamide

The mixture of methyl4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate(step-2 of Intermediate-9, 0.100 g, 0.280 mmol),1-[2-(trifluoromethyl)phenyl]methanamine (0.075 g, 0.430 mmol),1,2,4-traizole (0.004 g, 0.05 mmol) and DBU (0.009 g, 0.005 mmol) washeated at 80-90° C. in seal tube for 15 h. The reaction mass wasquenched in water and extracted with ethyl acetate. The organic layerwas washed with dilute HCl and water, dried over anhydrous sodiumsulphate and concentrated to afford 0.030 g of desired product. ¹H NMR(300 MHz, DMSO d₆): δ 4.66-4.68 (d, J=4.2 Hz, 2H), 7.45-7.75 (m, 7H),8.05 (s, 4H), 9.16 (br s, 1H), 12.73 (br s, 1H); MS (m/z): 489.42(M−H)⁻.

Example-195-[3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-Nyclopropylmethyl)-2-methoxybenzamide

The title compound was prepared according to the procedure described inExample-17 by using5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoicacid (Intermediate-11, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropylethyl amine (1.0 mL), TBTU (0.177 g, 0.540 mmol) and1-cyclopropylmethanamine (0.045 g, 0.410 mmol) to afford 0.035 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.23-0.24 (m, 2H),0.41-0.44 (m, 2H), 1.03 (m, 1H), 3.17 (t, J=7.2 Hz, 2H), 3.91 (s, 3H),7.25 (d, J=9.0 Hz, 1H), 7.49 (t, J=8.7 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H),7.65-7.70 (m, 1H), 7.98 (d, J=9.0 Hz, 1H), 8.23 (s, 1H), 8.32 (m, 1H),12.57 (s, 1H); MS (m/z): 415.23 (M−H)⁻.

Example-205-[3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxy-N-[2-(trifluoromethyl)benzyl]benzamide

The title compound was prepared according to the procedure described inExample-17 by using5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoicacid (Intermediate-11, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropylethyl amine (1.0 mL), TBTU (0.177 g, 0.540 mmol) and1-[2-(trifluoromethyl)phenyl]methanamine (0.072 g, 0.410 mmol) to afford0.035 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.95 (s, 3H),4.62-4.71 (br s, 2H), 7.30 (d, J=8.7 Hz, 1H), 7.46-7.52 (m, 2H),7.56-7.59 (m, 2H), 7.65-7.75 (m, 3H), 8.02 (dd, J=2.4 Hz, 1H), 8.28 (s,1H), 8.90 (br s, 1H), 12.58 (s, 1H); MS (m/z): 519.30 (M−H)⁻.

Example-215-[3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxy-N-{1-[2-(trifluoromethyl)phenyl]cyclopropyl}benzamide

The title compound was prepared according to the procedure described inExample-17 by using5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoicacid (Intermediate-11, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropylethyl amine (1.0 mL), TBTU (0.177 g, 0.540 mmol) and1-[2-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-12, 0.066 g,0.329 mmol) to afford 0.025 g of desired product. ¹H NMR (300 MHz, DMSOd₆): δ 1.26-1.28 (m, 4H), 3.91 (s, 3H), 7.24 (d, J=9.3 Hz, 1H),7.11-7.48 (m, 6H), 7.98 (t, J=7.5 Hz, 2H), 8.27 (s, 1H), 8.74 (s, 1H),12.56 (br s, 1H); MS (m/z): 545.31 (M−H)⁻.

Example-224-[3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}benzamide

The title compound was prepared according to the procedure described inExample-17 by using4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoicacid (Intermediate-9, 0.100 g, 0.290 mmol), THF (5 mL), di-isopropylethyl amine (2.0 mL), TBTU (0.193 g, 0.590 mmol) and1-[4-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-13, 0.073 g,0.350 mmol) to afford 0.030 g of desired product. ¹H NMR (300 MHz, DMSOd₆): δ 1.35 (s, 4H), 7.36 (d, J=7.8 Hz, 2H), 7.46-7.70 (m, 5H), 8.01 (s,4H), 9.30 (s, 1H), 12-13 (br s, 1H); MS (m/z): 515.23 (M−H)⁻.

Example-235-[3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxy-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}benzamide

The title compound was prepared according to the procedure described inExample-17 by using5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoicacid (Intermediate-11, 0.100 g, 0.270 mmol), THF (10 mL), di-isopropylethyl amine (10.0 mL), TBTU (0.177 g, 0.540 mmol) and1-[4-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-13, 0.066 g,0.320 mmol) to afford 0.025 g of desired product. ¹H NMR (300 MHz, DMSOd₆): δ 1.23 (s, 4H), 3.94 (s, 3H), 7.26 (d, J=9.0 Hz, 1H), 7.42 (d,J=8.4 Hz, 3H), 7.30-7.48 (m, 4H), 7.99 (d, J=9.3 Hz, 1H), 8.05 (s, 1H),8.96 (s, 1H), 12.51 (br s, 1H); MS (m/z): 547.15 (M⁺).

Example-244-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(1-(2-(trifluoromethyl)phenyl)cyclopropyl)benzamide

The title compound was prepared according to the procedure described inExample-17 by using4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoicacid (Intermediate-9, 0.100 g, 0.290 mmol), THF (10 mL), di-isopropylethyl amine (10.0 mL), TBTU (0.177 g, 0.540 mmol) and1-[2-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-12, 0.035 g,0.350 mmol) to afford 0.020 g of desired product. ¹H NMR (300 MHz, DMSOd₆): δ 1.23 (s, 2H), 1.31 (s, 2H), 7.59 (d, J=7.2 Hz, 2H), 7.65-7.68 (m,4H), 7.82 (d, J=12.0 Hz, 2H), 7.88-8.02 (m, 3H), 8.77 (s, 1H), 12.60 (brs, 1H); MS (m/z): 517.03 (M⁺).

Example-254-[3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxy-N-[2-(trifluoromethyl)benzyl]benzamide

The title compound was prepared according to the procedure described inExample-17 by using4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoicacid (Intermediate-15, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropylethyl amine (1.0 mL), TBTU (0.177 g, 0.540 mmol) and1-[2-(trifluoromethyl)phenyl]methanamine (0.072 g, 0.410 mmol) to afford0.025 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.96 (s, 3H),4.70 (d, J=4.8 Hz, 2H), 7.45-7.50 (m, 3H), 7.57 (t, J=8.4 Hz, 2H), 7.67(t, J=8.7 Hz, 2H), 7.71 (d, J=9.3 Hz, 2H), 7.92 (d, J=8.4 Hz, 1H), 8.80(t, 1H), 12.77 (br s, 1H); MS (m/z): 519.43 (M−H)⁻.

Example-264-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(1-(2-(trifluoromethyl)phenyl)cyclopropyl)benzamide

The title compound was prepared according to the procedure described inExample-17 by using4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoicacid (Intermediate-15, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropylethyl amine (2.0 mL), TBTU (0.177 g, 0.540 mmol) and1-[2-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-12, 0.082 g,0.410 mmol) to afford 0.020 g of desired product. ¹H NMR (300 MHz, DMSOd₆): δ 1.27-1.31 (m, 4H), 3.90 (s, 3H), 7.47 (t, J=8.1 Hz, 2H),7.54-7.69 (m, 6H), 7.87 (t, J=8.4 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.61(s, 1H); MS (m/z): 547.15 (M⁺).

Example-274-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)benzamide

The title compound was prepared according to the procedure described inExample-17 by using4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoicacid (Intermediate-15, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropylethyl amine (2.0 mL), TBTU (0.177 g, 0.540 mmol) and1-[4-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-13, 0.066 g,0.320 mmol) to afford 0.020 g of desired product. ¹H NMR (300 MHz, DMSOd₆): δ 1.37 (s, 4H), 3.95 (s, 3H), 7.42 (d, J=7.8 Hz, 2H), 7.50 (t,J=8.7 Hz, 1H), 7.63 (t, J=7.8 Hz, 4H), 7.73 (t, J=12.3 Hz, 3H), 8.85 (s,1H), 12.50 (br s, 1H); MS (m/z): 546.99 (M⁺).

Example-284-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-fluoro-2-(trifluoromethyl)benzyl)benzamide

The title compound was prepared according to the procedure described inExample-17 by using4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoicacid (Intermediate-9, 0.100 g, 0.30 mmol), THF (5 mL), di-isopropylethyl amine (2.0 mL), TBTU (0.177 g, 0.540 mmol) and4-fluoro-2-trifluoromethyl benzylamine (0.089 g, 0.600 mmol) to afford0.025 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 4.63 (d, J=4.5Hz, 2H), 7.48-7.50 (m, 6H), 8.05 (s, 4H), 9.16 (t, 1H), 12.67 (br, 1H);MS (m/z): 509.05 (M+H)⁺.

Example-294-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-(trifluoromethyl)phenyl)benzamide

To a solution of4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzamide(Intermediate-17, 0.100 g, 0.301 mmol) in dry toluene (5 mL) was added1-bromo-4-(trifluoromethyl)benzene (0.101 g, 0.451 mmol), sodiumtert-butoxide (0.058 g, 0.602 mmol),tris(diphynylideneacetone)dipalladium(0) (0.005 g, 0.0006 mmol), 4,5bis(diphenylphosphino) and 9,9-dimethylxanthene (0.005 g, 0.0009 mmol)under nitrogen atmosphere. The reaction mass was refluxed for 3-4 h. Thereaction mass was quenched in water and extracted in ethyl acetate. Theorganic layer was concentrated to afford crude product which waspurified by column chromatography to afford 0.015 g of desired product.¹H NMR (300 MHz, DMSO d₆): δ 7.40 (br s, 1H), 7.84 (t, J=9 Hz, 1H), 7.55(d, 1H), 7.72-7.75 (m, 3H), 8.02 (d, J=8.1 Hz, 2H), 8.11 (br s, 3H)10.61 (br s, 1H), 12.70 (br s, 1H). MS (m/z): 475.18 (M−H)⁻.

Example-303-(2-Chloro-6-fluorophenyl)-1-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one

To a solution of 4-fluoro-N′-hydroxybenzimidamide (Intermediate-18,0.073 g, 0.47 mmol) in dry DMF (3 mL) under nitrogen atmosphere wasadded4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzonitrile(step-4 of Intermediate-17, 0.100 g, 0.31 mmol) and ZnCl₂ (0.0087 g,0.06 mmol). The reaction mass was heated at 100° C. for 8-10 h. Thereaction mass was quenched with water, extracted in DCM and columnpurified to afford 0.025 g of desired product. ¹HNMR (DMSO-d₆): δ 7.02(br s, 1H), 7.33 (t, 1H), 7.45-7.54 (m, 2H), 7.61 (d, 1H), 7.70 (m, 1H),7.83 (t, 1H), 8.09-8.17 (m, 2H), 8.26-8.30 (m, 2H), 12.81 (br s, 1H). MS(m/z): 452.05 [M+H]⁺.

Example-314-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(trifluoromethyl)phenyl)benzamide

To a solution of methyl4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate(step-2 of Intermediate-9, 0.100 g, 0.28 mmol) in dry toluene was added3-trifloromethyl aniline (0.070 g, 0.43 mmol) followed by addition oftrimethyl aluminium (2M solution in toluene) (0.5 mL). The reactionmixture was refluxed for 1 h. The reaction mass was quenched in waterand acidified with dilute HCl and extracted in DCM. The organic layerwas dried over anhydrous sodium sulphate and concentrated to affordcrude product, which was column purified to afford 0.040 g of desiredproduct. ¹HNMR (DMSO-d₆): δ 7.45-7.54 (m, 2H), 7.59 (m, 2H), 7.72 (q,J=6.3 Hz, 1H), 8.05-8.12 (m, 5H), 8.25 (s, 1H), 10.58 (br s, 1H), 12.77(br s, 1H); MS (m/z): 477.08 [M+H]⁺.

Example-324-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)benzamide

The title compound was prepared according to the procedure described inExample-31, by using methyl4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate(step-2 of Intermediate-9, 0.100 g, 0.28 mmol),4-fluoro-3-trifloromethyl aniline (0.077 g, 0.43 mmol) and trimethylaluminium (2M solution in toluene) (0.5 mL) to afford 0.043 g of desiredproduct. ¹HNMR (DMSO-d₆): δ 7.46-7.59 (m, 3H), 7.69 (t, J=6.3 Hz, 1H),8.11 (br s, 5H), 8.26 (m, 1H), 10.59 (br s, 1H), 12.72 (br s, 1H); MS(m/z): 495.07 [M+H]⁺.

Example-334-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methoxybenzamide

The title compound was prepared according to the procedure described inExample-31, by using methyl4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-2 of Intermediate-15, 0.100 g, 0.26 mmol),4-floro-3-trifloromethyl aniline (0.070 g, 1.5 mmol), trimethylaluminium (2M solution in toluene) (0.5 mL) to afford 0.030 g of desiredproduct. ¹HNMR (DMSO-d₆): δ 3.94 (s, 3H), 7.50-7.60 (m, 3H), 7.67-7.72(m, 2H), 7.77-7.82 (m, 2H), 8.01 (m, 1H), 8.26 (m, 1H), 10.38 (br s,1H), 12.80 (br s, 1H); MS (m/z): 525.17 [M+H]⁺.

Example-344-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)benzamide

The title compound was prepared according to the procedure described inExample-31, by using methyl4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate(step-2 of Intermediate-9, 0.100 g, 0.28 mmol),2-fluoro-5-trifluoromethyl aniline (0.077 g, 0.43 mmol) and trimethylaluminium (2M solution in toluene) (0.5 mL) to afford 0.050 g of desiredproduct. ¹HNMR (DMSO-d₆): δ 7.48-7.61 (m, 3H), 7.68-7.73 (m, 2H),8.08-8.12 (m, 5H), 10.41 (br s, 1H), 12.78 (br s, 1H); MS (m/z): 493.09[M−H]⁻.

Example-354-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2-fluoro-4-methylphenyl)benzamide

The title compound was prepared according to the procedure described inExample-31, by using methyl4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate(step-2 of Intermediate-9, 0.100 g, 0.28 mmol), 2-fluoro-4-methylaniline (0.054 g, 0.43 mmol) and trimethyl aluminium (2M solution intoluene) (0.5 mL) to afford 0.055 g of desired product. ¹HNMR (DMSO-d₆):δ 2.30 (s, 3H), 7.00 (d, J=7.8 Hz, 1H), 7.11 (d, J=11.7 Hz, 1H),7.39-7.48 (m, 2H), 7.51-7.58 (d, 1H), 7.65-7.72 (m, 1H), 8.07 (br s,4H), 10.04 (br s, 1H), 12.73 (br s, 1H); MS (m/z): 439.13 [M−H]⁻.

Example-364-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)-2-methoxybenzamide

The title compound was prepared according to the procedure described inExample-31, by using methyl4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-2 of Intermediate-15, 0.100 g, 0.26 mmol),2-fluoro-5-trifluoromethyl aniline (0.070 g, 0.39 mmol) and trimethylaluminium (2M solution in toluene (0.5 mL) to afford 0.049 g of desiredproduct. ¹HNMR (DMSO-d₆): δ 4.05 (s, 3H), 7.50 (t, J=8.4 Hz, 1H),7.57-7.70 (m, 3H), 7.72-7.77 (m, 2H), 7.85 (s, 1H), 8.08 (d, J=8.4 Hz,1H), 8.67 (d, J=6.3 Hz, 1H), 10.38 (br s, 1H), 12.82 (br s, 1H); MS(m/z): 525.15 [M+H]⁺.

Example-37N-(5-Chloro-2-methylphenyl)-4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzamide

The title compound was prepared according to the procedure described inExample-31, by using methyl4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate(step-2 of Intermediate-9, 0.100 g, 0.28 mmol), 5-chloro-2-methylaniline (0.062 g, 0.43 mmol) and trimethyl aluminium (2M solution intoluene) (0.5 mL) to afford 0.059 g of desired product. ¹HNMR (DMSO-d₆):δ 2.23 (s, 3H), 7.23 (d, J=6.9 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.53 (m,2H), 7.59 (m, 1H), 7.71 (m, 1H), 8.10 (br s, 4H), 9.98 (br s, 1H), 12.76(br s, 1H); MS (m/z): 457.18 [M]⁺.

Example-38N-(5-Chloro-2-methylphenyl)-4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzamide

The title compound was prepared according to the procedure described inExample-31, by using methyl4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 5-chloro-2-methylaniline (0.057 g, 0.39 mmol) and trimethyl aluminium (2M solution intoluene) (0.5 mL) to afford 0.057 g of desired product. ¹HNMR (DMSO-d₆):δ 2.32 (s, 3H), 4.05 (s, 3H), 7.13 (d, J=9.9 Hz, 1H), 7.30 (d, J=8.1 Hz,1H), 7.49 (t, 1H), 7.59 (d, 1H), 7.61-7.75 (m, 2H), 7.84 (s, 1H), 8.08(d, J=8.7 Hz, 1H), 8.19 (s, 1H), 9.94 (br s, 1H), 12.83 (br s, 1H); MS(m/z): 487.11 [M]⁺.

Example-394-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2-fluoro-4-methylphenyl)-2-methoxybenzamide

The title compound was prepared according to the procedure described inExample-31, by using methyl4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 2-fluoro-4-methylaniline (0.050 g, 0.39 mmol) and trimethyl aluminium (2M solution intoluene) (0.5 mL) to afford 0.047 g of desired product. ¹HNMR (DMSO-d₆):δ 2.30 (s, 3H), 4.03 (s, 3H), 7.02 (d, J=8.1 Hz, 1H), 7.14 (d, J=11.7Hz, 1H), 7.51 (t, 1H), 7.58 (d, 1H), 7.65-7.75 (m, 2H), 7.85 (s, 1H),8.04-8.10 (m, 2H), 10.07 (br s, 1H), 12.65 (br s, 1H); MS (m/z): 469.16[M−H]⁻.

Example-403-(2-Chloro-6-fluorophenyl)-1-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one

To a solution of 4-chloro-N′-hydroxybenzimidamide (Intermediate-19,0.069 g, 0.39 mmol) in dry toluene was added sodium hydride (0.016 g,0.39 mmol). The reaction mixture was refluxed for 30 minutes followed byaddition of methyl4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-2 of Intermediate-15, 0.100 g, 0.26 mmol). The reaction mixturewas refluxed for 5-6 h. The reaction mixture was quenched in water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulphate and concentrated to afford crude product which wasfurther purified by column chromatography to afford 0.015 g of desiredproduct. ¹HNMR (DMSO-d₆): δ 3.98 (s, 3H), 7.45-7.48 (m, 1H), 7.54 (d,J=8.1 Hz, 1H), 7.67 (d, J=8.4 Hz, 3H), 7.83 (d, J=8.1 Hz, 1H), 7.95 (s,1H), 8.10 (d, J=8.4 Hz, 2H), 8.18 (d, J=8.7 Hz, 1H), 12.90 (br s, 1H).MS [M+H]⁺:499.89.

Example-413-(2-Chloro-6-fluorophenyl)-1-(4-(3-(3,5-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared by following the procedure as describedfor Example-40 by using methyl4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-2 of Intermediate-15, 0.100 g, 0.26 mmol),N′-hydroxy-3,5-dimethoxybenzimidamide (Intermediate-20, 0.077 g, 0.529mmol), sodium hydride (0.006 g, 0.39 mmol) and dry THF (5.0 mL) at RT toafford 0.015 g of desired product. ¹HNMR (DMSO-d₆): δ 3.84 (s, 6H), 3.99(s, 3H), 6.73 (s, 1H), 7.19 (s, 2H), 7.47 (t, J=8.1 Hz, 1H), 7.56 (d,J=8.4 Hz, 1H), 7.67 (t, J=8.7 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.93 (s,1H), 8.19 (d, J=8.7 Hz, 1H), 12.61 (br s, 1H); MS (m/z): 523.89 [M+]⁺.

Example-424-(3-(2,6-Dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-21, 0.100 g, 0.25 mmol), 3-(trifluoromethyl)aniline (0.062g, 0.38 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) anddry toluene (5.0 mL) to afford 0.035 g of desired product. ¹HNMR(DMSO-d₆): δ 3.95 (s, 3H), 7.45 (d, J=7.5 Hz, 1H), 7.59 (t, J=7.8 Hz,1H), 7.76-7.68 (m, 5H), 7.82 (t, J=8.7 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H),8.25 (s, 1H), 10.37 (s, 1H), 12.75 (br s, 1H); MS (m/z): 524.96 [M+H]⁺.

Example-434-(3-(2,6-Dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methoxybenzamide

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-21, 0.100 g, 0.25 mmol),4-fluoro-3-(trifluoromethyl)aniline (0.069 g, 0.38 mmol), trimethylaluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) toafford 0.050 g of desired product. ¹HNMR (DMSO-d₆): δ 4.09 (s, 3H), 7.52(t, J=9.6 Hz, 1H), 7.88-7.68 (m, 6H), 8.25 (s, 1H), 8.25 (d, J=6.9 Hz,1H), 10.37 (s, 1H), 12.74 (s, 1H); MS (m/z): 540.91 [M]⁺.

Example-444-(3-(2,6-Dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)-2-methoxybenzamide

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-21, 0.100 g, 0.25 mmol),2-fluoro-5-(trifluoromethyl)aniline (0.069 g, 0.38 mmol), trimethylaluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) toafford 0.035 g of desired product. ¹HNMR (DMSO-d₆): δ 4.06 (s, 3H), 7.59(d, J=7.8 Hz, 1H), 7.77-7.68 (m, 5H), 7.84 (s, 1H), 8.09 (d, J=8.7 Hz,1H), 8.67 (d, J=6.9 Hz, 1H), 10.38 (s, 1H), 12.79 (br s, 1H); MS (m/z):540.92 [M+H]⁺.

Example-454-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(6-fluorobenzo[d]thiazol-2-yl)-2-methoxybenzamide

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-2 of Intermediate-15, 0.100 g, 0.26 mmol),6-fluorobenzo[d]thiazol-2-amine (0.067 g, 0.397 mmol), trimethylaluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) toafford 0.050 g of desired product. ¹HNMR (DMSO-d₆): δ 3.99 (s, 3H), 7.32(t, J=7.2 Hz, 1H), 7.51 (t, J=9.3 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H),7.68-7.80 (m, 4H), 7.94 (t, J=6.3 Hz, 2H), 11.98 (s, 1H), 12.83 (br s,1H); MS (m/z): 512.97 [M−H]⁻.

Example-46N-(1H-Benzo[d]imidazol-2-yl)-4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzamide

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-2 of Intermediate-15, 0.100 g, 0.26 mmol),1H-benzo[d]imidazol-2-amine (0.046 g, 0.34 mmol), trimethyl aluminium(2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford0.040 g of desired product. ¹HNMR (DMSO-d₆): δ 4.01 (s, 3H), 7.11 (m,2H), 7.48-7.76 (m, 6H), 7.81 (s, 1H), 7.96 (d, J=9.0 Hz, 1H), 11.16 (brs, 1H), 12.28 (br s, 1H), 12.76 (br s, 1H); MS (m/z): 478.90 [M]⁺

Example-473-(2-Chloro-6-fluorophenyl)-1-(4-(3-(3-fluoro-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared by following the procedure as describedfor Example-40 by using methyl4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-2 of Intermediate-15, 0.100 g, 0.26 mmol),3-fluoro-N′-hydroxy-5-(trifluoromethyl)benzimidamide (Intermediate-22,0.088 g, 0.39 mmol), sodium hydride (0.017 g, 0.42 mmol) and dry THF(5.0 mL) at RT to afford 0.010 g of desired product. ¹HNMR (DMSO-d₆): δ4.01 (s, 3H), 7.50 (m, 1H), 7.60 (m, 1H), 7.70 (m, 1H), 7.84 (m, 1H),7.92 (br s, 1H), 8.02 (d, 1H), 8.18 (m, 2H), 8.25 (d, 1H), 12.95 (br s,1H); MS (m/z): 550.07 [M]⁺.

Example-484-(3-(2-Chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)benzamide

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-2 of Intermediate-15, 0.100 g, 0.26 mmol),5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine (0.059 g, 0.34 mmol),trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene(5.0 mL) to afford 0.025 g of desired product. ¹HNMR (DMSO-d₆): δ 3.95(s, 3H), 7.51 (t, J=9.0 Hz, 1H), 7.87-7.76 (m, 3H), 7.78 (s, 1H), 7.85(d, J=8.7 Hz, 1H), 12.86 (br s, 2H); MS (m/z): 514.90 [M]⁺.

Example-491-(4-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)-3-methoxyphenyl)-3-(2,6-dichlorophenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared by following the procedure as describedfor Example-40 by using methyl4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-21, 0.100 g, 0.25 mmol), 4-chloro-N-hydroxybenzimidamide(Intermediate-19, 0.064 g, 0.38 mmol), sodium hydride (0.020 g, 0.50mmol) and dry THF (5.0 mL) at RT to afford 0.015 g of desired product.¹HNMR (DMSO-d₆): δ 4.00 (s, 3H), 7.66-7.72 (m, 5H), 7.81 (d, J=8.7 Hz,1H), 7.89 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 8.22 (d, J=9.0 Hz, 1H), 12.82(br s, 1H); MS (m/z): 515.84 [M+H]⁺.

Example-503-(2,6-Dichlorophenyl)-1-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared by following the procedure as describedfor Example-40 by using methyl4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-21, 0.100 g, 0.25 mmol), N′-hydroxyisobutyrimidamide(0.077 g, 0.529 mmol), sodium hydride (0.020 g, 0.50 mmol) and dry THF(5.0 mL) at RT to afford 0.019 g of desired product. ¹HNMR (DMSO-d₆): δ1.31 (d, J=6.9 Hz, 6H), 3.12 (m, 1H), 3.95 (s, 3H), 7.65-7.78 (m, 4H),7.56 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 12.83 (br s, 1H); MS (m/z): 447.96[M+H]⁺.

Example-513-(2-Chloro-6-fluorophenyl)-1-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared by following the procedure as describedfor Example-40 by using methyl4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate(step-2 of Intermediate-9, 0.100 g, 0.28 mmol),4-chloro-N′-hydroxybenzimidamide (Intermediate-19, 0.073 g, 0.43 mmol),sodium hydride (0.018 g, 0.43 mmol) and dry THF (5.0 mL) to afford 0.025g of desired product. ¹HNMR (DMSO-d₆): δ 7.51 (t, J=8.7 Hz, 1H), 7.59(d, J=8.4 Hz, 1H), 7.67-7.73 (m, 3H), 8.11 (d, J=8.1 Hz, 2H), 8.24-8.29(m, 4H), 12.85 (br s, 1H); MS (m/z): 467.87 [M+H]⁺.

Example-524-(3-(2-Chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide

The title compound was prepared by following the procedure as describedfor step-2 of Intermediate-30 by using4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide(Intermediate-26, 0.060 g, 0.11 mmol), cyclopropylcarbonyl chloride(0.019 g, 0.17 mmol), DIPEA (1 mL) and THF (5 mL) to afford 0.020 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.06 (m, 2H), 1.22 (m,2H), 3.17 (m, 1H), 3.95 (s, 3H), 4.34 (d, J=6.0 Hz, 2H), 7.44-7.84 (m,8H), 7.95 (d, J=9.0 Hz, 1H), 8.25 (s, 1H), 8.70 (m, 1H), 10.43 (m, 1H),12.05 (m, 1H); MS (m/z): 584.35 (M+H⁺).

Example-534-(3-(2-Chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2-chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-27, 0.100 g, 0.268 mmol),3-(difluoromethyl)-4-fluoroaniline (Intermediate-28, 0.065 g, 0.403mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and drytoluene (5.0 mL) to afford 0.025 g of desired product. ¹H NMR (300 MHz,DMSO d₆): δ 2.32 (s, 3H), 3.94 (s, 3H), 7.05-7.41 (m, 3H), 7.50 (s, 2H),7.68-7.88 (m, 4H), 8.11 (m, 1H), 10.27 (s, 1H), 12.53 (s, 1H); MS (m/z):503.10 (M+H⁺).

Example-544-(3-(2-Chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)phenyl)-2-methoxybenzamide

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2-chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-27, 0.100 g, 0.268 mmol), 3-(difluoromethyl)aniline(Intermediate-29, 0.058 g, 0.40 mmol), trimethyl aluminium (2M solutionin toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.035 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 2.33 (s, 3H), 3.95 (s,3H), 7.04 (m, 1H), 7.35 (d, 1H), 7.41 (m, 1H), 7.50 (m, 3H), 7.69 (d,J=8.7 Hz, 1H), 7.77-7.82 (m, 3H), 8.07 (s, 1H), 10.25 (s, 1H), 12.52 (brs, 1H); MS (m/z): 485.06 (M+H⁺).

Example-553-(2-Chloro-6-methylphenyl)-1-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared by following the procedure as describedfor Example-40 by using methyl4-(3-(2-chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-27, 0.100 g, 0.26 mmol), 4-chloro-N′-hydroxybenzimidamide(Intermediate-19, 0.069 g, 0.40 mmol), sodium hydride (0.022 g, 0.53mmol) and dry THF (5.0 mL) to afford 0.020 g of desired product. ¹H NMR(300 MHz, DMSO d₆): δ 2.33 (s, 3H), 4.00 (s, 3H), 7.41 (m, 1H), 7.51 (s,2H), 7.67 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 1H), 7.90 (s, 1H), 8.10(d, J=8.4 Hz, 2H), 8.22 (d, J=8.7 Hz, 1H), 12.63 (s, 1H); MS (m/z):495.98 (M+H⁺).

Example-564-(3-(2-Chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2-chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-27, 0.100 g, 0.268 mmol), 3-(trifluoromethyl)aniline(0.040 g, 0.403 mmol), trimethyl aluminium (2M solution in toluene) (0.5mL) and dry toluene (5.0 mL) to afford 0.030 g of desired product. ¹HNMR (300 MHz, DMSO d₆): δ 2.33 (s, 3H), 3.95 (s, 3H), 7.41-7.59 (m, 4H),7.68 (t, J=6.9 Hz, 1H), 7.75 (d, 1H), 7.77-7.82 (m, 2H), 7.95 (d, J=8.4Hz, 1H), 8.25 (s, 1H), 10.36 (s, 1H), 12.53 (br s, 1H); MS (m/z): 503.17(M⁺).

Example-57N-(4-Chloro-3-(1-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanecarboxamide

The title compound was prepared by following the procedure as describedfor Example-40 by using methyl4-(3-(2-chloro-6-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-30, 0.100 g, 0.21 mmol), 4-chloro-N′-hydroxybenzimidamide(Intermediate-19, 0.056 g, 0.32 mmol), sodium hydride (0.018 g, 0.43mmol) and dry THF (5.0 mL) to afford 0.020 g of desired product. ¹H NMR(300 MHz, DMSO d₆): δ 1.21 (m, 2H), 1.59 (m, 2H), 3.04 (m, 1H), 3.98 (s,3H), 4.31 (m, 2H), 7.53 (m, 2H), 7.64 (m, 3H), 7.82 (m, 1H), 7.92 (m,1H), 8.08 (m, 2H), 8.20 (m, 1H), 8.67 (s, 1H), 12.77 (br s, 1H); MS(m/z): 577.07 (M+H⁺).

Example-583-(2-Chloro-6-fluorophenyl)-1-(3-methoxy-4-(1,5,6-trimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(step-2 of Intermediate-15, 0.100 g, 0.26 mmol),N¹,4,5-trimethylbenzene-1,2-diamine (Intermediate-31, 0.048 g, 0.32mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), drytoluene (5.0 mL) to afford 0.030 g of desired product. ¹H NMR (300 MHz,DMSO d₆): δ 2.33 (s, 3H), 2.36 (s, 3H), 3.56 (s, 3H), 3.85 (s, 3H), 7.33(s, 1H), 7.41 (s, 1H), 7.47-7.59 (m, 3H), 7.66-7.78 (m, 3H), 12.5 (br s,1H); MS (m/z): 478.29 (M+H⁺).

Example-593-(2-Chloro-6-fluorophenyl)-1-(4-((2,5-dichlorophenyl)ethynyl)-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared according to the procedure described inExample-3 using3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-32, 0.050 g, 0.11 mmol), 1,4-dichloro-2-ethynylbenzene(Intermediate-23, 0.029 g, 0.16 mmol), TBAF (0.101 g, 0.33 mmol),bis(triphenylphosphine)palladium(II) chloride (0.005 g, 0.04 mmol) andDMSO (3.0 mL) at 80° C. to afford 0.010 g of the desired product. ¹H NMR(300 MHz, DMSO d₆): δ 3.89 (s, 3H), 7.49-7.56 (m, 3H), 7.59-7.73 (m,6H), 12.90 (br s, 1H); MS (m/z): 487.95 (M+H⁺).

Example-601-(4-((3-Chloro-2-fluorophenyl)ethynyl)-3-methoxyphenyl)-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared according to the procedure described inExample-3 using3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-32, 0.050 g, 0.11 mmol),1-chloro-3-ethynyl-2-fluorobenzene

(Intermediate-24, 0.033 g, 0.22 mmol), TBAF (0.080 g, 0.30 mmol),bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol) andDMSO (3.0 ml) at 80° C. to afford 0.015 g of the desired product. ¹H NMR(300 MHz, DMSO d₆): δ 3.89 (s, 3H), 7.28 (t, J=7.8 Hz, 1H), 7.48 (t,J=9.0 Hz, 1H), 7.56-7.70 (m, 7H), 12.79 (m, 1H); MS (m/z): 470.00(M−H)⁻.

Example-611-(4-((2-Chloro-4-(trifluoromethyl)phenyl)ethynyl)-3-methoxyphenyl)-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared according to the procedure described inExample-3 using3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-32, 0.050 g, 0.11 mmol),2-chloro-1-ethynyl-4-(trifluoromethyl)benzene (Intermediate-25, 0.044 g,0.22 mmol), TBAF (0.080 g, 0.30 mmol),bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol) andDMSO (3.0 mL) at 80° C. to afford 0.012 g of desired product. ¹H NMR(300 MHz, DMSO d₆): δ 3.89 (s, 3H), 7.52 (t, J=9.0 Hz, 1H), 7.56-7.75(m, 6H), 7.83 (d, J=8.1 Hz, 1H), 8.02 (s, 1H), 12.78 (s, 1H); MS (m/z):522.00 (M+H)⁺.

Example-624-(3-(2-Chloro-6-cyanophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide

To a solution of4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide(Intermediate-34, 0.130 g, 0.211 mmol) in DMF (5 mL) was added CuCN(0.020 g, 0.232 mmol) and reaction mixture was heated at 80° C. for 4-5h. The reaction mass was quenched with aq. KMnO₄ solution and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulphate and concentrated to afford 0.015 g of desired product. ¹H NMR(300 MHz, DMSO d₆): δ 3.95 (s, 3H), 7.44 (d, J=7.8 Hz, 1H), 7.59 (t,J=8.4 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.80-7.86 (m, 3H), 7.95 (d, J=8.7Hz, 1H), 8.06-8.12 (m, 2H), 8.25 (s, 1H), 10.38 (s, 1H), 13.00 (br s,1H); MS (m/z): 512.14 (M−H)⁻.

Example-634-(3-(2-Chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide

The title compound was prepared by following the procedure as describedfor step-2 of Intermediate-30, by using4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide(Intermediate-35, 0.050 g, 0.09 mmol), cyclopropylcarbonyl chloride(0.016 g, 0.14 mmol), DIPEA (2.0 mL) and THF (5 mL) to afford 0.015 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.67 (s, 4H), 1.59 (m,1H), 3.92 (s, 3H), 3.32 (d, J=4.8 Hz, 2H), 7.03-7.33 (m, 1H), 7.35-7.47(m, 3H), 7.62-7.68 (m, 2H), 7.76-7.84 (m, 2H), 8.09 (m, 2H), 8.70 (m,1H), 10.28 (s, 1H), 12.69 (brs, 1H); MS (m/z): 586.12 (M+H)⁺.

Example-64N-(2-Chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzamide

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-21, 0.100 g, 0.25 mmol),N-(3-amino-4-chlorobenzyl)cyclopropanecarboxamide (Intermediate-36,0.085 g, 0.38 mmol), trimethyl aluminium (2M solution in toluene) (1 ml)and dry toluene (5.0 mL) to afford 0.020 g of desired product. ¹H NMR(300 MHz, DMSO d₆): δ 0.68 (d, J=8.1 Hz, 4H), 1.61 (m, 1H), 4.11 (s,3H), 4.28 (d, J=5.4 Hz, 2H), 7.04 (d, J=6.9 Hz, 1H), 7.52 (d, J=8.7 Hz,1H), 7.71-7.79 (m, 4H), 7.88 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.44 (s,1H), 8.67 (m, 1H), 10.53 (s, 1H), 12.82 (br s, 1H); MS (m/z): 587.96(M+H)⁺.

Example-653-(2,6-Dichlorophenyl)-1-(3-methoxy-4-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-21, 0.150 g, 0.30 mmol),4-(trifluoromethyl)benzene-1,2-diamine (0.081 g, 0.45 mmol), trimethylaluminium (2M solution in toluene) (2 mL), dry toluene (5.0 mL) toafford 0.015 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 4.09 (s,3H), 7.52 (s, 1H), 7.73-7.85 (m, 5H), 8.02-8.15 (m, 2H), 8.48 (m, 1H),12.79 (br s, 1H), 13.33 (br s, 1H); MS (m/z): 520.14 (M+H)⁺.

Example-66N-(4-Chloro-3-(1-(4-(cyclopropanecarboxamido)-3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanecarboxamide

The title compound was prepared by following the procedure as describedfor step-2 of Intermediate-30 by usingN-(3-(1-(4-amino-3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4-chlorobenzyl)cyclopropanecarboxamide(Intermediate-37, 0.050 g, 0.120 mmol), cyclopropylcarbonyl chloride(0.018 g, 0.180 mmol), DIPEA (2.0 mL) and THF (5 mL) to afford 0.015 gof desired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.69 (s, 4H), 0.77 (s,4H), 1.60 (m, 1H), 2.08 (m, 1H), 3.88 (s, 3H), 4.33 (d, J=5.4 Hz, 2H),7.45 (m, 2H), 7.62 (s, 2H), 7.96 (d, J=8.4 Hz, 1H), 8.69 (m, 1H), 9.49(s, 1H), 12.54 (s, 1H); MS (m/z): 482.10 (M+H)⁺.

Example-674-(3-(2,6-Dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(4-(methylsulfonyl)phenyl)benzamide

To a solution of4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(4-(methylthio)phenyl)benzamide(Intermediate-38, 0.070 g, 0.13 mmol) in mixture of acetonitrile:water(3 mL:3 mL) was added oxone (0.053 g, 0.34 mmol). The reaction mass wasstirred at RT for 24 h. The reaction mass was diluted with water andextracted with DCM. The organic layer was dried over anhydrous sodiumsulphate and concentrated to afford 0.020 g of desired product. ¹H NMR(300 MHz, DMSO d₆): δ 3.18 (s, 3H), 3.94 (s, 3H), 7.68-7.76 (m, 7H),7.80 (d, J=8.7 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H),10.48 (s, 1H), 12.76 (br s, 1H); MS (m/z): 531.14 (M+H)⁺.

Example-684-(3-(2-Chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)phenyl)-2-methoxybenzamide

The title compound was prepared by following the procedure as describedfor step-2 of Intermediate-30 by using4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)phenyl)-2-methoxybenzamide(Intermediate-39, 0.050 g, 0.10 mmol), cyclopropane carbonyl chloride(0.016 g, 0.15 mmol), DIPEA (2.0 mL) and THF (2 mL) to afford 0.015 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.68 (d, J=8.7 Hz, 4H),1.60 (m, 1H), 3.95 (s, 3H), 4.34 (d, J=5.4 Hz, 2H), 7.05 (m, 1H), 7.29(d, J=7.9 Hz, 1H), 7.41-7.55 (m, 4H), 7.65 (d, J=9.0 Hz, 1H), 7.74 (s,1H), 7.82 (d, J=8.7 Hz, 2H), 8.07 (s, 1H), 8.72 (m, 1H), 10.33 (s, 1H);MS (m/z): 566.29 (M−H)⁻.

Example-694-(3-(2-Chloro-5-(N-cyclopropylsulfamoyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2-chloro-5-(N-cyclopropylsulfamoyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-40, 0.040 g, 0.08 mmol), 3-(trifluoromethyl)aniline (0.020g, 0.12 mmol), trimethyl aluminium (2M solution in toluene) (1 ml) anddry toluene (5.0 mL) to afford 0.015 g of crude product, which waspurified by washing with methanol:DCM:DEE to afford 0.015 g of pureproduct. ¹H NMR (300 MHz, DMSO d₆): δ 0.42 (s, 2H), 0.54 (d, J=5.4 Hz,2H), 2.20 (m, 1H), 3.96 (s, 3H), 7.45 (d, J=7.5 Hz, 1H), 7.61 (t, 1H),7.70 (d, J=7.8 Hz, 1H), 7.80-7.84 (m, 2H), 7.96 (s, 3H), 8.18 (m, 2H),8.26 (s, 1H), 10.40 (s, 1H), 12.88 (br s, 1H); MS (m/z): 606.13 (M−H)⁻.

Example-704-(3-(2,6-Dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl4-(3-(2,6-dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate(Intermediate-41, 0.040 g, 0.09 mmol), 3-(trifluoromethyl)aniline (0.010g, 0.6 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) anddry toluene (5.0 mL) to afford 0.015 g of crude product which waspurified by column chromatography in basic alumina eluting with 0.2%methanol:DCM to afford 0.015 g of pure product. ¹H NMR (300 MHz, DMSOd₆): δ 1.14 (t, 3H), 3.55-3.57 (m, 2H), 3.95 (s, 3H), 7.46 (m, 1H), 7.59(t, 1H), 7.69-7.81 (m, 6H), 7.94 (m, 1H), 8.25 (s, 1H), 10.38 (s, 1H);MS (m/z): 551.11 (M+H)⁺.

Example-711-(4-((3-Chloro-2-fluorophenyl)ethynyl)phenyl)-3-(2-chloro-6-fluorophenyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared by following the procedure as describedfor Intermediate-41 by using1-(4-((3-chloro-2-fluorophenyl)ethynyl)phenyl)-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazol-5(4H)-one(Example-12, 0.070 g, 0.15 mmol), dry DMF (3 mL), NaH (0.010 g, 0.23mmol) and ethyl bromide (0.026 g, 0.23 mmol) to afford 0.030 g of thecrude product which was purified by column chromatography in basicalumina eluting with 0.2% methanol:DCM to afford 0.030 g of pureproduct. ¹H NMR (300 MHz, DMSO d₆): δ 1.09 (t, 3H), 3.56 (m, 2H), 7.29(t, 1H), 7.52-7.84 (m, 7H), 8.04 (d, J=8.1 Hz, 2H); MS (m/z): 470.06(M+H)⁺.

Example-724-(3-(2-Chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(trifluoromethyl)phenyl)benzamide

The title compound was prepared by following the procedure as describedfor Example-31 by using methyl 4-(3-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoate(Intermediate-42, 0.100 g, 0.24 mmol), 3-(trifluoromethyl)aniline (0.050g, 0.36 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) anddry toluene (8.0 mL). The reaction mass was quenched in water, extractedwith DCM and the organic layer was concentrated to afford 0.010 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.70 (s, 4H), 1.62 (m,1H), 4.33 (d, J=6.3 Hz, 2H), 7.44-7.67 (m, 4H), 8.10-8.26 (m, 6H), 8.68(m, 1H), 10.53 (s, 1H), 12.68 (br s, 1H); MS (m/z): 554.30 (M−H)⁻.

Example-734-(3-(2-Chloro-6-cyanophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methoxybenzamide

The title compound was prepared by following the procedure as describedfor Example-62 by using4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methoxybenzamide(Intermediate-43, 0.130 g, 0.21 mmol), DMF (4 mL) and CuCN (0.020 g,0.23 mmol) to afford 0.030 g of crude product which was further purifiedby column chromatography in basic alumina eluting with 50% methanol:DCMand few drops of 10% ammonia to afford 0.030 g of pure product. ¹H NMR(300 MHz, DMSO d₆): δ 3.94 (s, 3H), 7.52 (t, 1H), 7.68 (d, J=7.8 Hz,1H), 7.81 (m, 3H), 8.05-8.12 (m, 3H), 8.26 (s, 1H), 10.40 (s, 1H), 13.01(br s, 1H); MS (m/z): 532.12 (M+H)⁺.

Example-743-(4-((3-Chloro-2-fluorophenyl)ethynyl)-3-methoxyphenyl)-1-(2,6-dichlorophenyl)-1H-1,2,4-triazol-5(4H)-one

To a solution of1-(2,6-dichlorophenyl)-3-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-45, 0.070 g, 0.15 mmol) in DMSO (3.0 mL) was added1-chloro-3-ethynyl-2-fluorobenzene (Intermediate-24, 0.035 g, 0.22mmol), TBAF (0.080 g, 0.30 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol). Thereaction mass was stirred at 80° C. for 5-6 h. The reaction mass wasquenched in water and extracted with DCM and concentrated. The obtainedproduct was purified with column chromatography on silica gel elutingwith 2.0% EA:DCM to afford 0.020 g of the desired product. ¹H NMR (300MHz, DMSO d₆): δ 3.92 (s, 3H), 7.29 (t, J=8.4 Hz, 1H), 7.48-7.72 (m,8H), 12-13 (br s, 1H); MS (m/z): 488.00 (M⁺).

Example-753-(4-((2-Chloro-4-(trifluoromethyl)phenyl)ethynyl)-3-methoxyphenyl)-1-(2,6-dichlorophenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared according to the procedure described inExample-3 using1-(2,6-dichlorophenyl)-3-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-45, 0.070 g, 0.15 mmol),2-chloro-1-ethynyl-4-(trifluoromethyl)benzene (Intermediate-25, 0.046 g,0.22 mmol), TBAF (0.080 g, 0.30 mmol),bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol) andDMSO (3.0 mL) at 80° C. to afford 0.020 g of the desired product. ¹H NMR(300 MHz, DMSO d₆): δ 3.95 (s, 3H), 7.50-7.53 (m, 2H), 7.56-7.79 (m,5H), 7.88 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 12.04 (s, 1H); MS (m/z):538.07 (M⁺).

Example-764-(1-(2,6-Dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide

To a solution of methyl4-(1-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-methoxybenzoate(Intermediate-46, 0.070 g, 0.17 mmol) in dry toluene was added3-(trifluoromethyl)aniline (0.043 g, 0.17 mmol) followed by addition oftrimethyl aluminum (2M solution in toluene) (0.5 mL). The reactionmixture was refluxed for 1 hr under inert atmosphere. The reactionmixture was brought to RT and quenched with water. Few drops of diluteHCl were added and the reaction mixture was extracted with DCM andconcentrated. The obtained product was purified with columnchromatography to afford 0.050 g of desired product. ¹H NMR (300 MHz,DMSO d₆): δ 3.95 (s, 3H), 7.46 (d, J=6.9 Hz, 1H), 7.54-7.65 (m, 4H),7.72-7.76 (m, 3H), 7.94 (d, J=8.4 Hz, 1H), 8.24 (s, 1H), 10.51 (s, 1H),12.85 (s, 1H); MS (m/z): 523.04 (M⁺).

Example-774-(1-(2,6-Dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methoxybenzamide

The title compound was prepared by following the procedure as describedfor step-6 of Intermediate-26 by using methyl4-(1-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-methoxybenzoate(Intermediate-46, 0.070 g, 0.17 mmol),4-fluoro-3-(trifluoromethyl)aniline (0.048 g, 0.26 mmol), trimethylaluminum (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) toafford 0.040 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 3.95 (s,3H), 7.49-7.64 (m, 4H), 7.72-7.76 (m, 3H), 7.99 (m, 1H), 8.25 (m, 1H),10.52 (s, 1H), 12.86 (s, 1H); MS (m/z): 541.05 (M⁺).

Example-78N-(4-Chloro-3-(3-(4-((2,5-dichlorophenyl)ethynyl)-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide

The title compound was prepared according to the procedure described inExample-3 by usingN-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide(Intermediate-48, 0.060 g, 0.10 mmol), 1,4-dichloro-2-ethynylbenzene(Intermediate-23, 0.026 g, 0.15 mmol), TBAF (0.064 g, 0.20 mmol),bis(triphenylphosphine)palladium(II) chloride (0.064 g, 0.20 mmol) andDMSO (3.0 mL) at 80° C. to afford 0.020 g of the desired product. ¹H NMR(300 MHz, DMSO d₆): δ 0.68 (m, 4H), 1.60 (m, 1H), 4.33 (d, J=5.7 Hz,2H), 7.38 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.57-7.69 (m, 5H), 7.86-7.94(m, 2H), 8.68 (m, 1H), 12.45 (br s, 1H); MS (m/z): 557.05 (M+H⁺).

Example-79N-(4-Chloro-3-(3-(4-((4-chloro-2-fluorophenyl)ethynyl)-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide

The title compound was prepared according to the procedure described inExample-3 usingN-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide(Intermediate-48, 0.050 g, 0.097 mmol),4-chloro-1-ethynyl-2-fluorobenzene (Intermediate-49, 0.022 g, 0.14mmol), TBAF (0.061 g, 0.19 mmol), bis(triphenylphosphine)palladium(II)chloride (catalytic) and DMSO (1.0 mL) at 80° C. to afford 0.025 g ofthe desired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.65-0.68 (m, 4H),1.60 (m, 1H), 4.32 (d, J=6.0 Hz, 2H), 7.33-7.52 (m, 3H), 7.55-7.74 (m,5H), 7.90 (m, 1H), 8.68 (m, 1H), 12.0 (br s, 1H).; MS (m/z): 539.0 (M⁺).

Example-80N-(4-Chloro-3-(3-(2-fluoro-4-((3-(trifluoromethyl)phenyl)ethynyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide

The title compound was prepared according to the procedure described inExample-3 by usingN-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide(Intermediate-48, 0.050 g, 0.097 mmol),1-ethynyl-3-(trifluoromethyl)benzene (Intermediate-50, 0.025 g, 0.14mmol), TBAF (0.061 g, 0.19 mmol), bis(triphenylphosphine)palladium(II)chloride (catalytic) and DMSO (1.0 mL) at 80° C. to afford 0.020 g ofthe desired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.65-0.70 (m, 4H),1.60 (m, 1H), 4.31 (d, J=6.0 Hz, 2H), 7.28-7.41 (m, 2H), 7.51-7.61 (m,4H), 7.67-7.97 (m, 4H), 8.68 (m, 1H), 12.0 (br s, 1H); MS (m/z): 555.05(M+H⁺).

Example-81N-(4-Chloro-3-(3-(4-((3-chloro-2-fluorophenyl)ethynyl)-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide

The title compound was prepared according to the procedure described inExample-3 usingN-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide(Intermediate-48, 0.050 g, 0.097 mmol),1-chloro-3-ethynyl-2-fluorobenzene (Intermediate-24, 0.022 g, 0.14mmol), TBAF (0.061 g, 0.19 mmol), bis(triphenylphosphine)palladium(II)chloride (catalytic) and DMSO (1.0 mL) at 80° C. to afford 0.030 g ofthe desired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.69 (m, 4H), 1.60 (m,1H), 4.33 (d, J=5.7 Hz, 2H), 7.30-7.41 (m, 3H), 7.48-7.74 (m, 5H),7.87-7.93 (m, 1H), 8.69 (m, 1H), 12.40-12.58 (br s, 1H); MS (m/z):539.36 (M⁺).

Example-82N-(4-Chloro-3-(3-(4-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide

The title compound was prepared according to the procedure described inExample-3 by usingN-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide(Intermediate-48, 0.060 g, 0.117 mmol),2-chloro-1-ethynyl-4-(trifluoromethyl)benzene (Intermediate-25, 0.037 g,0.175 mmol), TBAF (0.073 g, 0.234 mmol),bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (1.0mL) at 80° C. to afford 0.030 g of the desired product. ¹H NMR (300 MHz,DMSO d₆): δ 0.66-0.69 (m, 4H), 1.60 (m, 1H), 4.33 (d, J=6.0 Hz, 2H),7.40 (d, J=8.4 Hz, 1H), 7.48 (s, 1H), 7.62-7.64 (m, 2H), 7.73 (d, J=11.4Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.92-7.97 (m, 2H), 8.09 (s, 1H), 8.69(m, 1H), 12.00 (br s, 1H); MS (m/z): 589.14 (M⁺).

Example-83N-(4-Chloro-3-(1-(3,4-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide

To a solution of tert-butyl 2-(3,4-dichlorophenyl)hydrazinecarboxylate(Intermediate-52, 0.060 g, 0.21 mmol) in DCM (10 mL) was added solutionof 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate(Intermediate-51, 0.101 g, 0.32 mmol) in DCM and the reaction mixturewas stirred for 20 h at room temperature, followed by addition of TFA (3mL) and further stirred for 20 h at room temperature. The reaction masswas quenched in water, extracted with DCM and concentrated to affordcrude product which was purified by column chromatography eluting withMeOH:DCM to afford 0.007 g of pure product. ¹H NMR (300 MHz, CDCl₃): δ1.20 (s, 9H), 4.44 (d, J=5.4 Hz, 2H), 6.20 (m, 1H), 7.29 (m, 1H),7.41-7.49 (m, 2H), 7.91 (d, J=8.1 Hz, 1H), 8.15 (s, 1H); MS (m/z):471.26 (M⁺).

Example-84N-(4-Chloro-2-fluoro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53,0.060 g, 0.21 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoylisocyanate (Intermediate-51, 0.101 g, 0.32 mmol), DCM (10 mL) and TFA (3mL) to afford 0.025 g of pure product. ¹H NMR (300 MHz, CDCl₃): δ 1.19(s, 9H), 4.40 (m, 2H), 6.22 (m, 1H), 7.26 (m, 1H), 7.35 (m, 1H), 7.62(d, J=8.1 Hz, 2H), 8.12 (d, J=7.8 Hz, 2H); MS (m/z): 471.18 (M+H⁺).

Example-85N-(4-Chloro-3-(1-(2,4-difluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl2-(2,4-difluorophenyl)hydrazinecarboxylate (Intermediate-54, 0.060 g,0.21 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate(Intermediate-51, 0.101 g, 0.32 mmol), DCM (10 mL) and TFA (3 mL) toafford 0.018 g of pure product. ¹H NMR (300 MHz, CDCl₃): δ 1.16 (s, 9H),4.38 (d, J=5.4 Hz, 2H), 6.25 (m, 1H), 6.79-6.82 (m, 1H), 6.90-6.96 (m,2H), 7.20-7.32 (m, 2H), 7.50-7.53 (m, 1H); MS (m/z): 437.26 (M−H⁻).

Example-86N-(4-Chloro-2-fluoro-3-(1-(4-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl2-(4-methoxyphenyl)hydrazinecarboxylate (Intermediate-55, 0.060 g, 0.21mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate(Intermediate-51, 0.101 g, 0.32 mmol), DCM (10 mL) and TFA (3 mL) toafford 0.018 g of pure product. ¹H NMR (400 MHz, CDCl₃): δ 1.20 (s, 9H),3.82 (s, 3H), 4.46 (d, J=5.8 Hz, 2H), 6.12 (m, 1H), 6.95 (d, J=8.9 Hz,2H), 7.26-7.30 (m, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.82 (d, J=8.9 Hz, 2H),11.01 (br s, 1H); MS (m/z): 433.20 (M+H⁺).

Example-87N-(4-Chloro-2-fluoro-3-(3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)pivalamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate(Intermediate-57, 0.050 g, 0.13 mmol),2-fluoro-4-(trifluoromethyl)benzoyl isocyanate (Intermediate-56, 0.10 g,0.26 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.030 g of pureproduct. ¹H NMR (400 MHz, CDCl₃): δ 1.20 (s, 9H), 4.48 (d, J=5.7 Hz,2H), 6.13 (m, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.41-7.51 (m, 3H), 8.12 (t,J=7.9 Hz, 1H); MS (m/z): 489.20 (M+H⁺).

Example-88N-(4-Chloro-3-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)pivalamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate(Intermediate-57, 0.050 g, 0.13 mmol), 2-chloro-6-fluorobenzoylisocyanate (Intermediate-8, 0.060 g, 0.26 mmol), DCM (10 mL) and TFA (3mL) to afford 0.025 g of pure product. ¹H NMR (400 MHz, CDCl₃): δ 1.19(s, 9H), 4.48 (m, 2H), 6.09 (m, 1H), 7.15 (t, J=8.4 Hz, 1H), 7.32 (t,J=8.2 Hz, 2H), 7.40-7.45 (m, 2H), 10.66 (br s, 1H); MS (m/z): 455.21(M⁺).

Example-89N-(4-chloro-3-(1-(4-cyanophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl 2-(4-cyanophenyl)hydrazinecarboxylate(step-2 of Intermediate 17, 0.060 g, 0.25 mmol),6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate(Intermediate-51, 0.160 g, 0.51 mmol), DCM (10 mL) and TFA (3 mL) toafford 0.020 g of pure product. ¹H NMR (400 MHz, CDCl₃): δ 1.20 (s, 9H),4.45 (d, J=5.9 Hz, 2H), 6.19 (m, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.43 (t,J=7.9 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 8.19 (d, J=8.4 Hz, 2H), 10.72 (brs, 1H); MS (m/z): 426.27 (M−H⁻).

Example-90N-(4-Chloro-3-(3-(4-chloro-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)pivalamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate(Intermediate-57, 0.050 g, 0.13 mmol), 4-chloro-2-fluorobenzoylisocyanate (Intermediate-58, 0.060 g, 0.26 mmol), DCM (10 mL) and TFA (3mL) to afford 0.025 g of desired product. ¹H NMR (400 MHz, CDCl₃): δ1.21 (s, 9H), 4.50 (t, J=7.2 Hz, 2H), 6.07 (m, 1H), 7.22-7.26 (m, 2H),7.32 (d, J=8.4 Hz, 1H), 7.44 (t, J=8.1 Hz, 1H), 7.93 (t, J=8.6 Hz, 1H);MS (m/z): 455.08 (M⁺).

Example-91N-(4-Chloro-3-(3-(4-chloro-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)hydrazinecarboxylate(step-7 of Intermediate-48, 0.060 g, 0.17 mmol),4-chloro-2-fluorobenzoyl isocyanate (Intermediate-58, 0.035 g, 0.71mmol), DCM (10 mL) and TFA (3 mL) to afford 0.040 g of desired product.¹H NMR (400 MHz, DMSO d₆): δ 0.67-0.69 (m, 4H), 1.59-1.60 (m, 1H), 4.31(d, J=5.9 Hz, 2H), 7.36 (dd, J=6.24 Hz, 1H), 7.45 (dd, J=8.5 Hz, 2H),7.59 (d, J=8.3 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.83 (t, J=8.3 Hz, 1H),7.64 (t, J=6 Hz, 1H), 12.51 (br s, 1H); MS (m/z): 421.08 (M⁺).

Example-92N-(4-Chloro-3-(3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)hydrazinecarboxylate(step-7 of Intermediate-48, 0.060 g, 0.17 mmol),2-fluoro-4-(trifluoromethyl)benzoyl isocyanate (Intermediate-56, 0.035g, 0.82 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.045 g of desiredproduct. ¹H NMR (400 MHz, DMSO d₆): δ 0.67 (m, 4H), 1.60 (m, 1H), 4.3(d, J=5.9 Hz, 2H), 7.37 (d, J=6.4 Hz, 1H), 7.46 (s, 1H), 7.60 (d, J=8.3Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.89 (d, J=10.56 Hz, 1H), 8.05 (t,J=7.7 Hz, 1H), 8.65 (t, J=5.8 Hz, 1H), 12.6 (br s, 1H); MS (m/z): 454.98(M⁺).

Example-93N-(4-Chloro-2-fluoro-3-(5-oxo-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)pivalamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate(Intermediate-57, 0.050 g, 0.13 mmol), 4-(trifluoromethyl)benzoylisocyanate (Intermediate-59, 0.060 g, 0.26 mmol), DCM (10 mL) and TFA (3mL) to afford 0.045 g of desired product. ¹H NMR (400 MHz, DMSO d₆): δ1.12 (s, 9H), 4.30 (d, J=4.4 Hz, 2H), 7.41 (t, J=8 Hz, 1H), 7.53 (d,J=8.5 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 8.0 (d, J=8.2 Hz, 2H), 8.17 (t,J=5.8 Hz, 1H), 12.9 (br s, 1H); MS (m/z): 471.10 (M+H⁺).

Example-94N-(4-Chloro-2-fluoro-3-(5-oxo-1-(5-(trifluoromethyl)pyridin-2-yl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl2-(5-(trifluoromethyl)pyridin-2-yl)hydrazinecarboxylate(Intermediate-60, 0.050 g, 0.18 mmol),6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate(Intermediate-51, 0.120 g, 0.36 mmol), DCM (10 mL) and TFA (3 mL) toafford 0.012 g of desired product. ¹H NMR (400 MHz, DMSO d₆): δ 1.13 (s,9H), 4.30 (d, J=5.6 Hz, 2H), 7.11 (br s, 1H), 7.46 (t, J=8 Hz, 1H), 7.52(d, J=8.8 Hz, 1H), 8.14 (m, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.35 (dd, J=7.2Hz, 1H), 8.87 (s, 1H); MS (m/z): 472.24 (M+H⁺).

Example-95N-(4-Chloro-2-fluoro-3-(5-oxo-1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl 2-(6-(trifluoromethyl)pyridin-3-yl)hydrazine carboxylate (Intermediate-61, 0.050 g, 0.18 mmol),6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate(Intermediate-51, 0.120 g, 0.36 mmol), DCM (10 mL) and TFA (3 mL) toafford 0.013 g of desired product. ¹H NMR (400 MHz, DMSO d₆): δ 1.13 (s,9H), 4.30 (d, J=5.6 Hz, 2H), 7.11 (br s, 1H), 7.46 (t, J=8 Hz, 1H), 7.53(d, J=8.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 8.16 (m, 1H), 8.56 (dd, J=6.4Hz, 1H), 9.30 (m, 1H); MS (m/z): 472.26 (M+H⁺).

Example-964-Chloro-N-cyclopropyl-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzenesulfonamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53,0.050 g, 0.18 mmol), 2-chloro-5-(N-cyclopropylsulfamoyl)benzoylisocyanate (step-4 of Intermediate-40, 0.108 g, 0.36 mmol), DCM (10 mL)and TFA (3 mL) to afford 0.050 g of desired product. ¹H NMR (400 MHz,DMSO d₆): δ 0.40-0.42 (m, 2H), 0.50-0.54 (m, 2H), 2.17-2.21 (m, 1H),7.85 (d, J=8.8 Hz, 2H), 7.92-7.98 (m, 2H), 8.15-8.21 (m, 4H), 12.84 (s,1H); MS (m/z): 457.15 (M+H⁺).

Example-974-Chloro-3-(1-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-N-cyclopropylbenzenesulfonamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl2-(4-chlorophenyl)hydrazinecarboxylate (Intermediate-62, 0.050 g, 0.20mmol), 2-chloro-5-(N-cyclopropylsulfamoyl)benzoyl isocyanate (step-4 ofIntermediate-40, 0.123 g, 0.41 mmol), DCM (10 mL) and TFA (3 mL) toafford 0.025 g of pure product. ¹H NMR (400 MHz, DMSO d₆): δ 0.39-0.41(m, 2H), 0.49-0.52 (m, 2H), 2.17-2.20 (m, 1H), 7.52-7.55 (d, J=8.0 Hz,2H), 7.91-8.00 (m, 5H), 8.14 (m, 1H), 12.60 (br s, 1H); MS (m/z): 425.10(M⁺).

Example-98N-(4-Chloro-3-(1-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl2-(4-chlorophenyl)hydrazinecarboxylate (Intermediate-62, 0.050 g, 0.20mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate(Intermediate-51, 0.130 g, 0.41 mmol), DCM (10 mL) and TFA (3 mL) toafford 0.040 g of pure product. ¹H NMR (400 MHz, DMSO d₆): δ 1.12 (s,9H), 4.30 (d, J=6.0 Hz, 2H), 7.24-7.47 (m, 2H), 7.52 (d, J=7.2 Hz, 2H),7.94 (d, J=8.8 Hz, 2H), 8.16 (m, 1H), 12.10 (br s, 1H); MS (m/z): 437.16(M⁺).

Example-99N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described forExample-83 by using tert-butyl2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 1.00g, 3.63 mmol), 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoylisocyanate (step-3 of Intermediate-26, 1.30 g, 4.03 mmol), DCM (20 mL)and TFA (5.0 mL) to afford 0.700 g of the desired product. ¹H NMR (400MHz, DMSO d₆): δ 4.44-4.46 (d, J=6 Hz, 2H), 7.48-7.50 (d, J=8.4 Hz, 1H),7.65-7.68 (m, 2H), 7.84-7.86 (d, J=8.8 Hz, 2H), 8.17-8.19 (d, J=8.4 Hz,2H), 10.05 (br s, 1H), 12.69 (br s, 1H); MS (m/z): 463.17 (M−H⁻).

Example-100N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

To a solution of3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-63, 0.070 g, 0.189 mmol) in dry THF (5 mL) was added DIPEA(3 mL) and stirred for 20 minutes. The reaction mixture was cooled to 0°C. and pivaloyl chloride (0.025 g, 0.283 mmol) was added and stirred for3 h at RT. The reaction mass was quenched in water, extracted withDCM:MeOH and concentrated to afford of the crude product which waspurified by column chromatography eluting with MeOH:DCM to afford 0.030g of the desired title product. ¹H NMR (400 MHz, DMSO d₆): δ 1.12 (s,9H), 4.28-4.30 (d, J=6 Hz, 2H), 7.39-7.42 (d, J=8. Hz, 1H), 7.59-7.61(d, J=6.4 Hz, 2H), 7.84-7.86 (d, J=8.8 Hz, 2H), 8.14-8.19 (m, 3H), 12.59(br s, 1H); MS (m/z): 451.29 (M−H⁻).

Example-101(R)—N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)tetrahydrofuran-2-carboxamide

To a solution of3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-63, 0.070 g, 0.189 mmol) in dry THF:DMF (4:1 mL) was addedTBTU (0.182 g, 0.567 mmol) and TEA (3 mL) and stirred for 1 h undernitrogen atmosphere. To the reaction mixture (R)-(+)tetrahydro-2-furoicacid (0.032 g, 0.283 mmol) was added and stirred for 18 h at roomtemperature. The reaction mass was quenched in water, extracted withethyl acetate and concentrated to afford crude product which waspurified by column chromatography eluting with MeOH:DCM to afford 0.025g of the desired title product. ¹H NMR (400 MHz, DMSO d₆): δ 1.23 (s,2H), 1.74-1.92 (m, 3H), 2.09-2.24, (m, 1H), 3.75-3.80 (m, 1H), 3.89-3.94(m, 1H), 4.26-4.37 (m, 3H), 7.43-7.45 (d, J=8.4 Hz, 1H), 7.61-7.63 (d,J=8.4 Hz, 2H), 7.85-7.87 (d, J=8.8 Hz, 2H), 8.19-8.21 (d, J=8.8 Hz, 2H),8.50-8.53 (m, 1H), 12.71 (br s, 1H); MS (m/z): 465.55 (M−H⁻).

Example-102N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanesulfonamide

The title compound was prepared according to the procedure described inExample-100 by using3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-63, 0.070 g, 0.189 mmol), cyclopropanesulfonyl chloride(0.2 mL), DIPEA (3 mL), and dry THF (5 mL) to afford 0.029 g of pureproduct. ¹H NMR (400 MHz, DMSO d₆): δ 0.86-0.92 (m, 4H), 1.14-1.24 (m,1H), 4.26-4.28 (d, J=6.4 Hz, 2H), 7.57-7.60 (d, J=8.4 Hz, 1H), 7.63-7.68(d, J=8.4 Hz, 1H), 7.58-7.81 (m, 1H), 7.86-7.88 (d, J=8.8 Hz, 2H),8.19-8.21 (d, J=8.4 Hz, 2H), 12.89 (br s, 1H); MS (m/z): 471.30 (M−H⁻).

Example-103N-(4-Chloro-3-(1-cyclohexyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide

The title compound was prepared by following the procedure as describedfor Example-83 by using tert-butyl 2-(cyclohexyl)hydrazinecarboxylate(Intermediate-64, 0.050 g, 0.23 mmol),6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate(Intermediate-51, 0.225 g, 0.70 mmol), DCM (10 mL) and TFA (3 mL) toafford 0.015 g of pure product. ¹H NMR (400 MHz, DMSO d₆): δ 1.13 (s,9H), 1.22-1.23 (m, 2H), 1.30-1.37 (m, 2H), 1.62-1.64 (m, 2H), 1.78-1.81(m, 4H), 3.90-3.92 (m, 1H), 4.27-4.28 (d, J=4.8 Hz, 2H), 7.37-7.41 (t,1H), 7.46-7.48 (d, 1H), 8.17 (br s, 1H); MS (m/z): 409.36 (M+H⁺).

Example-104N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2-fluorobenzamide

To a solution of3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-63, 0.060 g, 0.162 mmol) in dry THF (5 mL) was added DIPEA(3 mL) and stirred for 20 minutes. The reaction mixture was cooled to 0°C. and 2-fluorobenzoyl chloride (0.038 g, 0.243 mmol) was added andstirred for 3 h at room temperature. The reaction mass was quenched inwater, extracted with DCM:MeOH and concentrated to afford crude productwhich was purified by column chromatography eluting with MeOH:DCM toafford 0.030 g of pure product. ¹H NMR (400 MHz, DMSO d₆): δ 4.50-4.52(d, J=8 Hz, 2H), 7.25-7.33 (m, 2H), 7.52-7.55 (m, 2H), 7.63-7.65 (m,2H), 7.72-7.86 (d, J=2.4 Hz, 1H), 7.83-7.86 (d, J=11.6 Hz, 2H),8.17-8.20 (d, J=11.6 Hz, 2H), 8.95-8.99 (t, 1H), 12.69 (br s, 1H); MS(m/z): 491.17 (M+H+).

Example-105N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)isoxazole-5-carboxamide

To a solution of3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-63, 0.060 g, 0.162 mmol) in dry THF (5 mL) was added DIPEA(3 mL) and stirred for 20 minutes. The reaction mixture was cooled to 0°C. and isoxazole-5-carbonyl chloride (0.032 g, 0.243 mmol) was added andstirred for 3 h at room temperature. The reaction mass was quenched inwater, extracted with DCM: MeOH and concentrated to afford crude productwhich was purified by column chromatography eluting with MeOH:DCM toafford 0.030 g of pure product. ¹H NMR (400 MHz, DMSO d₆): δ 4.50-4.52(d, J=8 Hz, 2H), 7.09-7.10 (d, J=2 Hz, 1H), 7.43-7.45 (d, J=8.4 Hz, 1H),7.50-7.53 (d, J=10.4 Hz, 1H), 7.59-7.64 (d, J=18 Hz, 1H), 7.82-7.85 (d,J=8.8 Hz, 2H), 8.17-8.19 (d, J=8.4 Hz, 2H), 8.74-8.75 (d, J=2 Hz, 1H),9.58-9.61 (t, 1H), 12.61-12.74 (br s, 1H); MS (m/z): 464.11 (M+H+).

Example-106N-(3-(1-(4-(Trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using tert-butyl2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 1.00g, 3.63 mmol), 3-((2,2,2-trifluoroacetamido)methyl)-2,6-dimethylbenzoylisocyanate (Intermediate-65, 1.00 g, 3.33 mmol), DCM (20 mL), trifluoroacetic acid (5.0 mL) to afford 0.700 g of the desired product. ¹H NMR(400 MHz, DMSO d₆): δ 2.20 (s, 3H), 2.22 (s, 3H), 4.40 (d, J=4.2 Hz,2H), 7.21 (d, J=6.0 Hz, 1H), 7.29 (d, J=6.0 Hz, 1H), 7.82 (d, J=6.6 Hz,1H), 8.17 (d, J=6.6 Hz, 1H), 9.95 (t, J=6.9 Hz, 1H), 12.32 (br s, 1H);MS (m/z): 457.26 (M−H)⁻.

Example-107(R)—N-(2,4-Dimethyl-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)tetrahydrofuran-2-carboxamide

To a solution of5-(3-(aminomethyl)-2,6-dimethylphenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-66, 0.050 g, 0.138 mmol) in dry THF:DMF (4 mL:1 mL), TBTU(0.132 g, 0.414 mmol) and TEA (1.0 mL) were added and the reaction masswas stirred for 1 h under nitrogen atmosphere. To the reaction mass,(R)-(−)-tetrahydrofuran-2-carboxylic acid (0.024 g, 0.207 mmol) wasadded and stirred for 18 h at room temperature. After completion of thereaction, the reaction mass was quenched in water, extracted with ethylacetate and concentrated to afford crude product which was purified bycolumn chromatography by eluting with solution of 2% ammonia in 10%MeOH:DCM to afford 0.017 g of the title product. ¹H NMR (400 MHz, DMSOd₆): δ 1.79 (m, 3H), 1.87 (m, 3H), 2.20 (s, 6H), 3.74-3.79 (m, 1H),3.88-3.92 (m, 1H), 4.25 (d, J=4.5 Hz, 2H), 7.16 (d, J=6.0 Hz, 1H), 7.25(d, J=6.0 Hz, 1H), 7.82 (d, J=6.6 Hz, 1H), 8.17 (d, J=6.3 Hz, 2H), 8.24(t, J=4.8 Hz, 2H), 12.30 (br s, 1H); MS (m/z): 461.14 (M+H)⁺.

Example-108N-(3-(1-(4-(Trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)pivalamide

To a solution of5-(3-(aminomethyl)-2,6-dimethylphenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-66, 0.050 g) in dry THF (5 mL), TEA (3 mL) was added andstirred the reaction mixture for 20 minutes. The reaction mixture wascooled to 0° C. and pivaloyl chloride (0.05 g, 0.563 mmol) was added andstirred for 3 h at RT. After completion of the reaction, the reactionmass was quenched with water, extracted with DCM:MeOH. The organic layerwas separated, concentrated, and purified by column chromatography toafford 0.012 g of the desired title product. ¹H NMR (400 MHz, DMSO d₆):δ 1.15 (s, 9H), 2.18 (s, 3H), 2.22 (s, 3H), 4.24 (d, J=12.6 Hz, 2H),7.19 (d, 1H), 7.25 (d, 1H), 7.84 (d, J=5.7 Hz, 2H), 8.0 (t, 1H), 8.20(d, J=6.4 Hz, 2H), 12.30 (br s, 1H); MS (m/z): 447.20 (M+H)⁺.

Example-109

(S)—N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-tetrahydrofuran-2-carboxamide

The title compound was prepared according to the procedure described inExample-107 by using3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-63, 0.070 g, 0.189 mmol), THF:DMF (5 mL:1 mL),(S)-(−)tetrahydrofuran-2-carboxylic acid (0.032 g, 0.283 mmol), TBTU(0.182 g, 0.567 mmol), and TEA (3.0 mL). The obtained crude was purifiedby column chromatography on basic alumina by eluting solution of 2%ammonia in 10.0% MeOH:DCM to afford 0.010 g of the desired product. ¹HNMR (300 MHz, DMSO d₆): δ 1.80 (m, 3H), 2.15 (m, 1H), 3.75 (m, 1H), 3.94(m, 1H), 4.27-4.32 (m, 3H), 7.42 (d, 1H), 7.60 (d, 2H), 7.85 (d, J=5.4Hz, 2H), 8.20 (d, J=4.5 Hz, 2H), 8.52 (s, 1H), 12.50 (s, 1H); MS (m/z):467.08 (M+H)⁺.

Example-110N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-1-methyl-1H-imidazole-2-carboxamide

The title compound was prepared according to the procedure described inExample-108 by using3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-63, 0.070 g, 0.189 mmol), 1-methyl-1H-imidazole-2-carbonylchloride (0.026 g, 0.283 mmol), dry THF (5 mL), DIPEA (2 mL). Theobtained crude was purified by column chromatography using 2% ammonia in20% MeOH:DCM as mobile phase to afford 0.020 g of the desired titleproduct. ¹H NMR (300 MHz, DMSO d₆): δ 3.50 (s, 3H), 4.41 (d, J=18.0 Hz,1H), 6.99 (s, 1H), 7.43 (br, 2H), 7.67 (d, 1H), 7.78 (s, 1H), 8.28 (d,J=4.5 Hz, 2H), 8.30 (s, 1H), 9.08 (t, 1H); MS (m/z): 477.10 (M+H)⁺.

Example-111N-(4-Chloro-2-fluoro-3-(4,5-dihydro-3-(4-(3,3-dimethylbut-1-ynyl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

To a solution ofN-(4-chloro-2-fluoro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide(Intermediate-68, 0.050 g, 0.094 mmol) in DMSO (3.0 mL),3,3-dimethylbut-1-yne (0.011 g, 0.142 mmol), TBAF (0.074 g, 0.283 mmol)and bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol)were added and the reaction mass was stirred at 80° C. for 5-6 h. Aftercompletion of the reaction, the reaction mass was quenched with waterand extracted with DCM and concentrated. The obtained crude product waspurified with column chromatography on silica gel column and 2.0% EA:DCMas mobile phase to afford 0.022 g of the desired title product. ¹H NMR(400 MHz, DMSO d₆): δ 1.09 (s, 9H), 1.25 (s, 9H), 4.31 (br s, 2H),7.35-7.51 (m, 4H), 7.80 (d, J=8.3 Hz, 2H), 8.18-8.20 (m, 1H); MS (m/z):481.14 (M−H)⁻.

Example-112N-(4-Chloro-3-(3-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-2-fluorobenzyl)pivalamide

The title compound was prepared according to the procedure described inExample-111 by usingN-(4-chloro-2-fluoro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide(Intermediate-68, 0.050 g, 0.094 mmol), ethynylcyclopropane (0.009 g,0.142 mmol), TBAF (0.074 g, 0.283 mmol),bis(triphenylphosphine)palladium(II) chloride (0.003 g, 0.003 mmol) andDMSO (3.0 mL) to afford 0.018 g of the desired title product. ¹H NMR(400 MHz, DMSO d₆): δ 0.75 (m, 2H), 0.77-0.91 (m, 2H), 1.36 (s, 9H),1.53-1.59 (m, 2H), 7.38 (t, J=5.9 Hz, 1H), 7.46-7.52 (m, 3H), 8.79 (d,J=4.4 Hz, 2H), 8.19 (t, J=4.3 Hz, 1H); MS (m/z): 467.15 (M+H)⁺.

Example-113N-(4-Chloro-2-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using tert-butyl2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53,0.300 g), 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoylisocyanate (Intermediate-69, 0.300 g), DCM (20 mL), trifluoro aceticacid (5.0 mL) to afford 0.030 g of the desired product. ¹H NMR (400 MHz,DMSO d₆): δ 4.49 (m, 2H), 7.74-7.77 (m, 1H), 7.78-7.80 (m, 1H), 7.87 (d,J=5.1 Hz, 2H), 8.19 (d, J=4.2 Hz, 2H), 10.06 (m, 1H), 12.76 (s, 1H); MS(m/z): 467.15 (M+H)⁺.

Example-114N-(4-Chloro-2-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-70, 0.080 g, 0.206 mmol), pivaloyl chloride (0.027 g,0.227 mmol), THF (5.0 mL) and TEA (0.2 mL) to afford 0.043 g of thedesired product. ¹H NMR (400 MHz, DMSO d₆): δ 1.13 (s, 9H), 4.31-4.32(m, 2H), 7.86 (d, J=6.5 Hz, 2H), 8.13-8.18 (m, 3H), 12.70 (s, 1H); MS(m/z): 471.14 (M+H)⁺.

Example-115N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-3-hydroxy-2,2-dimethylpropanamide

The title compound was prepared according to the procedure described inExample-107 by using3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-63, 0.100 g, 0.271 mmol), THF:DMF (5 mL:1 mL),3-methoxy-2,2-dimethylpropanoic acid (0.053 g, 0.407 mmol), TBTU (0.261g, 0.813 mmol), TEA (2.0 mL). The obtained crude was purified by columnchromatography using basic alumina as stationary phase and eluting withthe solution of 2% ammonia in 10.0% MeOH:DCM to afford 0.012 g of thedesired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.05 (s, 6H), 3.30 (s,2H), 4.30 (d, J=4.5 Hz, 1H), 4.36 (s, 1H), 7.53 (d, J=6.3 Hz, 1H), 7.75(s, 1H), 8.08 (t, J=4.5 Hz, 1H), 8.21 (d, J=6.3 Hz, 2H); MS (m/z):469.04 (M+H)⁺.

Example-116N-(4-Chloro-3-(1-(4-chloro-3-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using tert-butyl2-(4-chloro-3-fluorophenyl)hydrazinecarboxylate (Intermediate-71, 0.828g, 0.003 mmol), 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoylisocyanate (step-3 of Intermediate-26, 1.3 g, 0.043 mmol), DCM (20 mL),trifluoro acetic acid (5.0 mL) to afford 0.500 g of the desired product.¹H NMR (300 MHz, DMSO d₆): δ 4.45 (d, 2H), 7.48 (d, J=15.0 Hz, 1H),7.68-7.83 (m, 3H), 7.85 (d, 1H), 7.99 (d, J=17.1 Hz, 1H), 10.08 (d,J=12.0 Hz, 1H), 12.73 (s, 1H).

Example-117N-(4-Chloro-3-(4,5-dihydro-1-(4,4-dimethylcyclohexyl)-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using 4,4-dimethyl tert-butyl 2-cyclohexylhydrazinecarboxylate (Intermediate-72, 0.269 g, 1.1 mmol),2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-2of Intermediate-26, 0.400 g, 1.2 mmol), DCM (20 mL), trifluoro aceticacid (5.0 mL) to afford 0.200 g of the desired product. ¹H NMR (300 MHz,DMSO d₆): δ 1.33 (s, 6H), 1.43-1.91 (m, 8H), 3.86-3.94 (m, 1H), 4.41 (d,J=4.5 Hz, 2H), 7.38 (d, J=7.5 Hz, 1H), 7.53 (s, 1H), 7.58 (d, J=6.3 Hz,1H), 10.02-10.04 (m, 1H), 11.95 (s, 1H); MS (m/z): 431.17 (M+H)⁺.

Example-118N-(4-Chloro-3-(4,5-dihydro-1-(4,4-dimethylcyclohexyl)-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

To a solution of5-(5-(aminomethyl)-2-chlorophenyl)-2-(4,4-dimethylcyclohexyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-73, 0.070 g, 0.202 mmol) in dry THF (5.0 mL), DIPEA (2.0mL) and pivaloyl chloride (0.30 g, 0.242 mmol) were added and thereaction mass was stirred at RT for 16 h. After completion of thereaction, the reaction mass was quenched with water and extracted with10% MeOH:DCM. The organic layer was washed with dilute HCl andconcentrated. The obtained crude was purified with column chromatographyon basic alumina by eluting with 2.0% MeOH:DCM to afford 0.040 g of thedesired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.44 (s, 6H), 1.47 (s,9H), 1.81-1.94 (m, 8H), 3.86-3.90 (m, 1H), 4.40 (s, 2H), 7.33 (d, J=1.5Hz, 1H), 7.45 (s, 1H), 7.50 (d, J=2.1 Hz, 1H), 8.16 (t, 1H), 11.93 (s,1H); MS (m/z): 419.21 (M+H)⁺.

Example-119(R)—N-(4-chloro-2-fluoro-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)tetrahydrofuran-2-carboxamide

The title compound was prepared according to the procedure described inExample-107 by using5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-70, 0.090 g, 0.233 mmol), THF:DMF (5 mL:1 mL),(R)-(−)-tetrahydrofuran-2-carboxylic acid (0.040 g, 0.349 mmol), TBTU(0.224 g, 0.699 mmol), and TEA (0.5 mL). The obtained crude was purifiedwith column chromatography using basic alumina as stationary phase and2% ammonia in 10.0% MeOH:DCM solution as mobile phase to afford 0.015 gof the desired product. ¹H NMR (400 MHz, DMSO d₆): δ 1.78-1.91 (m, 2H),2.09-2.15 (m, 1H), 3.74 (m, 1H), 3.88-3.94 (m, 1H), 4.28 (m, 1H), 4.43(m, 2H), 7.65 (m, 2H), 7.86 (d, J=8.72 Hz, 2H), 8.18 (d, J=8.52 Hz, 2H),8.45 (d, J=16.0 Hz, 1H), 12.71 (s, 1H).

Example-120N-(3-(1-tert-Butyl-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-4-chlorobenzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using tert-butyl 2-tert-butylhydrazinecarboxylate(Intermediate-74, 0.233 g, 1.2 mmol),2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3of Intermediate-26, 0.400 g, 1.2 mmol), DCM (10 mL), trifluoro aceticacid (5.0 mL) to afford 0.100 g of the desired product. ¹H NMR (400 MHz,DMSO d₆): δ 1.52 (s, 9H), 4.42 (s, 2H), 7.39 (d, 1H), 7.41 (s, 1H), 7.58(d, J=2.1 Hz, 2H), 10.0 (br s, 1H), 12.0 (br s, 1H); MS (m/z): 377.20(M+H)⁺.

Example-121N-(3-(1-tert-Butyl-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-4-chlorobenzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using2-tert-butyl-5-(5-(aminomethyl)-2-chlorophenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-75, 0.250 g), pivaloyl chloride (1.0 mL), DIPEA (2.0 mL),and dry THF (5 mL) to afford 0.180 g of desired product. ¹H NMR (400MHz, DMSO d₆): δ 1.08 (s, 9H), 1.49 (s, 9H), 4.24 (d, J=4.5 Hz, 2H),7.32 (dd, J=4.5 Hz, 3.6 Hz, 2H), 7.43 (s, 1H), 7.50 (s, 1H), 8.14 (d,J=4.5 Hz, 1H); MS (m/z): 365.20 (M+H)⁺.

Example-122N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-3-methoxy-2,2-dimethylpropanamide

To a solution of3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-63, 0.250 g, 0.678 mmol) in THF:DMF (5 mL:1 mL), TBTU(0.653 g, 2.3 mmol), TEA (4.0 mL) were added and the reaction mass wasstirred at RT for 1 h. To the reaction mixture,3-methoxy-2,2-dimethylpropanoic acid (0.134 g, 1.01 mmol) was added andstirring was continued at RT for 2 days. After completion of thereaction, the reaction mass was quenched with water and extracted withethyl acetate. The organic layer was separated, dried and concentratedto obtain crude product. The obtained crude was purified with columnchromatography on basic alumina by eluting with 5.0% MeOH:DCM to afford0.110 g of the desired product. ¹H NMR (400 MHz, DMSO d₆): δ 1.15 (s,6H), 1.18 (s, 3H), 3.09 (t, 2H), 4.32 (d, J=11.4 Hz, 2H), 7.43 (dd,J=4.5 Hz, 3.6 Hz, 1H), 7.45 (d, 1H), 7.86 (d, J=5.4 Hz, 2H), 8.15 (t,1H), 8.20 (d, 2H), 12.50 (br s, 1H); MS (m/z): 483.20 (M+H)⁺.

Example-123N-(4-Chloro-3-(1-(4-chloro-3-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chlorophenyl)-2-(4-chloro-3-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-76, 0.250 g), pivaloyl chloride (1.0 mL), DIPEA (2.0 mL),dry THF (5 mL) to afford 0.110 g of the desired product. ¹H NMR (400MHz, DMSO d₆): δ 1.24 (s, 9H), 4.30 (d, J=14.7 Hz, 2H), 7.40 (dd, J=4.5Hz, 3.6 Hz, 1H), 7.43 (d, 1H), 7.60 (d, J=5.4 Hz, 1H), 7.74 (d, 1H),7.98 (d, 1H), 8.18 (t, J=15.0 Hz, 11H), 12.70 (s, 1H); MS (m/z): 437.59(M+H)⁺.

Example-124N-(4-Chloro-2-fluoro-5-(4,5-dihydro-1-(4,4-dimethylcyclohexyl)-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-83 by using 4,4-dimethyl tert-butyl 2-cyclohexylhydrazinecarboxylate (Intermediate-72, 0.400 g),5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate(Intermediate-69, 0.400 g), DCM (10 mL), trifluoro acetic acid (5.0 mL)to afford 0.150 g of the desired product. ¹H NMR (400 MHz, DMSO d₆): δ0.93 (s, 6H), 1.32-1.35 (m, 2H), 1.36-1.46 (m, 2H), 1.59-1.62 (m, 2H),1.83-1.87 (m, 2H), 3.89 (m, 1H), 4.42 (m, 2H), 7.72 (m, 2H), 10.0 (s,1H), 12.01 (s, 1H); MS (m/z): 449.48 (M+H)⁺.

Example-125N-(4-Chloro-2-fluoro-5-(4,5-dihydro-1-(4,4-dimethylcyclohexyl)-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4,4-dimethylcyclohexyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-77, 0.200 g), pivaloyl chloride (0.5 mL), TEA (2.0 mL),dry THF (5 mL) to afford 0.033 g of the desired product. ¹H NMR (300MHz, CDCl₃): δ 1.36 (s, 6H), 1.37 (s, 9H), 1.62 (m, 2H), 1.79 (m, 1H),1.82 (m, 2H), 1.89 (m, 2H), 3.46-3.94 (m, 1H), 4.28 (s, 2H), 7.47 (d,J=7.9 Hz, 1H), 7.59 (d, J=9.72 Hz, 1H), 8.15 (m, 1H), 11.95 (s, 1H); MS(m/z): 436.55 (M+H)⁺.

Example-126N-(4-Chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-chlorophenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-78, 0.120 g), pivaloyl chloride (0.5 mL), TEA (2.0 mL),dry THF (5 mL) to afford 0.033 g of the desired product. ¹H NMR (300MHz, DMSO): δ 1.12 (s, 9H), 4.30 (br s, 2H), 7.53-7.63 (m, 4H), 7.95 (d,J=12.8 Hz, 2H), 8.14 (s, 1H), 12.61 (s, 1H); MS (m/z): 437.47 (M+H)⁺.

Example-127N-(4-Chloro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-methoxybenzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chloro-4-methoxyphenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-79, 0.200 g), pivaloyl chloride (0.2 mL), TEA (2.0 mL),dry THF (5 mL) to afford 0.015 g of the desired product. ¹H NMR (300MHz, CDCl₃): δ 1.15 (s, 9H), 3.91 (s, 3H), 4.22 (m, 2H), 7.26 (s, 1H),7.42 (s, 1H), 7.87 (m, 2H), 7.99 (m, 1H), 8.15 (m, 2H), 12.57 (s, 1H);MS (m/z): 483.38 (M+H)⁺.

Example-128N-(4-Chloro-2-fluoro-5-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-81, 0.300 g), pivaloyl chloride (0.3 mL), TEA (2.0 mL),dry THF (5 mL) to afford 0.065 g of the desired product. ¹H NMR (300MHz, CDCl₃): δ 1.12 (s, 9H), 4.30 (m, 2H), 7.61-7.69 (m, 3H), 8.16 (brs, 1H), 8.25 (br s, 2H), 12.73 (s, 1H); MS (m/z): 489.47 (M+H)⁺.

Example-129N-(4-Chloro-2-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-82, 0.300 g), pivaloyl chloride (0.3 mL), TEA (2.0 mL),dry THF (10 mL) to afford 0.050 g of the desired product. ¹H NMR (300MHz, CDCl₃): δ 1.12 (s, 9H), 4.31 (d, J=6.8 Hz, 2H), 7.63-7.71 (m, 2H),8.05-8.07 (m, 1H), 8.16 (m, 1H), 8.55 (d, J=13.2 Hz, 1H), 9.29 (s, 1H),12.85 (s, 1H); MS (m/z): 472.41 (M+H)⁺.

Example-130N-(2,4-Dichloro-5-(3-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-111 usingN-(2,4-dichloro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide(Intermediate-84, 0.150 g, 0.028 mmol), ethynylcyclopropane (0.038 g,0.56 mmol), TBAF (0.268 g, 0.85 mmol),bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (3.0mL) to afford 0.050 g of the desired product. ¹H NMR (300 MHz, DMSO d₆):δ 0.77 (m, 2H), 0.93 (m, 2H), 1.21 (s, 9H), 1.58 (m, 1H), 4.32 (d, J=6.3Hz, 2H), 7.50-7.53 (m, 3H), 7.82-7.91 (m, 2H), 7.95 (s, 1H), 8.21 (m,1H)

Example-131N-(4-Chloro-5-(1-(3-chloro-4-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(3-chloro-4-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-86, 0.300 g), pivaloyl chloride (0.3 mL), TEA (2.0 mL),dry THF (10 mL) to afford 0.083 g of the desired product. ¹H NMR (300MHz, DMSO): δ 1.13 (s, 9H), 4.30 (d, J=6.4 Hz, 2H), 7.53-7.66 (s, 3H),7.91-8.15 (s, 3H), 12.67 (s, 1H); MS (m/z): 455.19 (M+H)⁺.

Example-132N-(4-Chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-2-fluorobenzamide

A mixture of 2-fluoro benzoic acid (0.400 g), thionyl chloride (20 mL)and DMF (cat. amt.) was refluxed for 5 h and excess of solvent wasremoved under reduced pressure to obtain crude product. The obtainedcrude product was added to the solution of5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-chlorophenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-78, 0.250 g) and DIPEA (1.0 mL) in THF (20 mL) and thereaction mass was stirred for 3 h. After completion of reaction,reaction mass was quenched with water and extracted with ethyl acetate.The organic layer was separated, concentrated to afford 0.032 g of thedesired product. ¹H NMR (300 MHz, DMSO): δ 4.53 (br s, 2H), 7.29 (m,2H), 7.70 (m, 3H), 7.78 (m, 3H), 7.95 (br s, 2H), 8.94 (br s, 1H), 12.63(br s, 1H); MS (m/z): 475.39 (M+H)⁺.

Example-133N-(4-Chloro-2-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)isobutyramide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-70, 0.100 g), 2-methylpropanoyl chloride (0.1 mL), TEA(0.1 mL), dry THF (5 mL) to afford 0.028 g of the desired product. ¹HNMR (300 MHz, DMSO): δ 1.01 (s, 6H), 4.32 (d, J=7.6 Hz, 2H), 7.67-7.71(m, 2H), 7.85 (d, J=11.2 Hz, 2H), 8.17 (d, J=11.6 Hz, 2H), 8.36 (m, 1H),12.73 (s, 1H); MS (m/z): 457.37 (M+H)⁺.

Example-134N-(4-Chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-3-fluoro-2,2-dimethylpropanamide

Step-1:—Preparation ofN-(4-chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-3-hydroxy-2,2-dimethylpropanamide

The title compound was prepared according to the procedure described inExample-107 by using5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-chlorophenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-78, 0.250 g, 0.708 mmol), THF:DMF (5 mL:1 mL),3-hydroxy-2,2-dimethylpropanoic acid (0.091 g, 0.407 mmol), TBTU (0.340g, 1.062 mmol), TEA (2.0 mL) to afford 0.150 g of the desired product.¹H NMR (300 MHz, CDCl₃): δ 1.05 (s, 6H), 2.68 (s, 2H), 4.32 (d, J=8.0Hz, 2H), 7.53 (d, J=12.0 Hz, 2H), 7.64-7.67 (m, 2H), 7.95-7.98 (m, 2H),8.08 (br s, 1H); MS (m/z): 453.27 (M⁺H)⁺.

Step-2:—PreparationN-(4-chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-3-fluoro-2,2-dimethylpropanamide

To a solution ofN-(4-chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-3-hydroxy-2,2-dimethylpropanamide(0.150 g, 0.330 mmol) in THF (5.0 mL), DAST (0.079 g, 0.495 mmol) wasadded at 0-5° C. and stirred at RT for 5-6 h. After completion of thereaction, the reaction mass was quenched with water and extracted withethyl acetate. The organic layer was separated, concentrated and theobtained crude was purified with column chromatography using basicalumina by eluting with solution of 2% ammonia in 10.0% MeOH:DCM toafford 0.013 g of the desired product. ¹H NMR (300 MHz, CDCl₃): δ 1.13(s, 6H), 4.32 (m, 3H), 4.46 (s, 1H), 7.55 (m, 2H), 7.69 (m, 2H),7.94-7.97 (m, 2H), 8.31 (s, 1H), 12.61 (s, 1H); MS (m/z): 454.25 (M+H)⁺.

Example-135N-(4-Chloro-5-(1-(3-chloro-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-88, 0.200 g), pivaloyl chloride (0.5 mL), TEA (2.0 mL),dry THF (5 mL) to afford 0.074 g of the desired product. ¹H NMR (300MHz, DMSO d₆): δ 1.11 (s, 9H), 2.32 (s, 3H), 4.29 (d, J=8.8 Hz, 2H),7.43 (d, J=11.6 Hz, 1H), 7.60-7.67 (m, 1H), 7.79 (d, J=10.4 Hz, 1H),7.96 (s, 1H), 8.15 (m, 1H), 12.60 (s, 1H); MS (m/z): 451.52 (M+H)⁺.

Example-136N-(4-Chloro-5-(3-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-2-fluorobenzyl)pivalamide

The title compound was prepared according to the procedure described inExample-111 usingN-(4-chloro-2-fluoro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide(Intermediate-90, 0.200 g, 0.370 mmol), ethynylcyclopropane (0.050 g,0.75 mmol), TBAF (0.360 g, 1.13 mmol),bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (3.0mL) at 80° C. to afford 0.080 g of the desired product. ¹H NMR (300 MHz,DMSO d₆): δ 0.77 (br s, 9H), 0.92 (br s, 2H), 1.10 (s, 3H), 1.57 (m,1H), 4.30 (d, J=5.4 Hz, 2H), 7.43-7.50 (m, 3H), 7.65 (d, J=5.4 Hz, 2H),7.77 (d, J=5.1 Hz, 2H), 12.57 br s, 1H); MS (m/z): 467.36 (M+H)⁺.

Example-137N-(4-Chloro-2-fluoro-5-(4,5-dihydro-3-(4-(3,3-dimethylbut-1-ynyl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-111 usingN-(4-chloro-2-fluoro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide(Intermediate-90, 0.100 g, 0.189 mmol), 3,3-dimethylbut-1-yne (0.031 g,0.378 mmol), TBAF (0.178 g, 0.567 mmol),bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (3.0mL) to afford 0.050 g of the desired product. ¹H NMR (300 MHz, DMSO d₆):δ 1.10 (s, 9H), 1.30 (s, 9H), 4.30 (d, J=9.0 Hz, 2H), 7.43-7.50 (m, 3H),7.65 (d, J=9.3 Hz, 1H), 7.78 (d, J=8.1 Hz, 2H), 8.14 (br s, 1H), 12.60(br s, 1H); MS (m/z): 483.29 (M+H)⁺.

Example-138N-(4-Chloro-3-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chlorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-91, 0.350 g, 0.945 mmol), pivaloyl chloride (0120 g, 0.945mmol), DIPEA (2.0 mL), dry THF (10 mL) to afford 0.080 g of the desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 1.11 (s, 9H), 4.30 (d, J=6.3 Hz,2H), 7.43 (d, J=8.4 Hz, 1H), 7.61-7.64 (m, 2H), 8.06 (d, J=9.0 Hz, 1H),8.19 (m, 1H), 8.58 (d, J=8.4 Hz, 1H), 9.32 (s, 1H), 12.82 (s, 1H); MS(m/z): 454.50 (M+H)⁺.

Example-139N-(4-Chloro-3-(1-(3-chloro-4-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-chloro-4-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-92, 0.300 g, 0.852 mmol), pivaloyl chloride (0.108 g,0.852 mmol), DIPEA (2.0 mL), dry THF (10 mL) to afford 0.050 g of thedesired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.13 (s, 9H), 4.29 (d,J=5.4 Hz, 2H), 7.40 (d, J=7.8 Hz, 1H), 7.52-7.59 (m, 3H), 7.91-8.18 (m,3H), 12.65 (s, 1H); MS (m/z): 437.23 (M+H)⁺.

Example-140N-(4-Chloro-3-(1-(3-chloro-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-93, 0.350 g, 1.00 mmol), pivaloyl chloride (0.128 g, 1.0mmol), DIPEA (2.0 mL), dry THF (10 mL) to afford 0.200 g of the desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 1.13 (s, 9H), 2.34 (s, 3H), 4.29(d, J=6.3 Hz, 2H), 7.39-7.47 (m, 2H), 7.58-7.61 (m, 2H), 7.82 (d, J=8.7Hz, 1H), 8.01 (s, 1H), 8.18 (t, 1H), 12.58 (s, 1H); MS (m/z): 433.19(M+H)⁺.

Example-141N-(4-Chloro-3-(3-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

To a solution ofN-(4-chloro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide(Intermediate-95, 0.100 g, 0.196 mmol) in DMSO (3.0 mL),ethynylcyclopropane (0.035 g, 0.530 mmol), TBAF (0.150 g, 0.574) andbis(triphenylphosphine)palladium(II) chloride_(catalytic) were added andthe reaction mass was stirred at 80° C. for 5-6 h. After completion ofthe reaction, the reaction mass was quenched with water and extractedwith DCM and concentrated to afford 0.050 g of the desired titleproduct. ¹H NMR (300 MHz, DMSO d₆): δ 0.76-0.91 (m, 2H), 0.91-0.92 (m,2H), 1.11 (s, 9H), 1.57 (m, 1H), 4.28 (br d, 2H), 7.31-7.34 (br d, 1H),7.42 (br s, 1H), 7.47-7.50 (br m, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.78 (d,J=8.4 Hz, 2H), 8.18 (s, 1H), 12.58 (s, 1H); MS (m/z): 449.52 (M+H)⁺.

Example-142N-(4-Chloro-3-(1-(3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-96, 0.250 g, 0.678 mmol), pivaloyl chloride (0.3 mL), TEA(2.0 mL), and dry THF (5 mL) to afford 0.150 g of the desired product.¹H NMR (300 MHz, DMSO d₆): δ 1.13 (s, 9H), 4.30 (d, J=6.0 Hz, 2H),7.41-7.43 (m, 1H), 7.59-7.62 (m, 3H), 7.71-7.76 (m, 1H), 8.19-8.29 (m,3H), 12.68 (s, 1H); MS (m/z): 453.38 (M+H)⁺.

Example-143N-(4-Chloro-3-(4,5-dihydro-3-(4-(3,3-dimethylbut-1-ynyl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide

The title compound was prepared according to the procedure described inExample-111 by usingN-(4-chloro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide(Intermediate-98, 0.060 g, 0.120 mmol), 3,3-dimethylbut-1-yne (0.014 g,0.181 mmol), TBAF (0.094 g, 0.362 mmol),bis(triphenylphosphine)palladium (II)chloride (0.003 g, 0.003 mmol) andDMSO (3.0 mL) to afford 0.015 g of the desired product. ¹H NMR (400 MHz,DMSO d₆): δ 1.03 (s, 6H), 1.30 (s, 9H), 2.50 (m, 1H), 4.27 (d, J=5.4 Hz,2H), 7.35 (d, J=8.7 Hz, 1H), 7.44-7.50 (m, 3H), 7.61 (d, J=8.1 Hz, 1H),7.80 (d, J=8.1 Hz, 2H), 8.38 (m, 1H); MS (m/z): 449.9 (M−H)⁻.

Example-144N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)isobutyramide

The title compound was prepared according to the procedure described inExample-108 by using3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-63, 0.250 g, 0.678 mmol), isobutyryl chloride (0.108 g,1.01 mmol), TEA (2.0 mL), and dry THF (5 mL) to afford 0.350 g of thedesired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.14 (d, J=6.6 Hz, 6H),2.41-2.43 (m, 1H), 4.30 (d, J=6.3 Hz, 2H), 7.43 (d, J=8.1 Hz, 1H),7.61-7.64 (m, 2H), 7.86 (d, J=9.3 Hz, 2H), 8.20 (d, J=8.4 Hz, 2H), 8.38(m, 1H), 12.69 (s, 1H); MS (m/z): 43924 (M+H)⁺.

Example-145N-(4-Chloro-3-(3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-83 by using tert-butyl2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate(Intermediate-94, 0.150 g, 0.420 mmol), 4-(trifluoromethyl)benzoylisocyanate (Intermediate-59, 0.181 g, 0.84 mmol), DCM (15 mL), andtrifluoro acetic acid (3.0 mL) to afford 0.070 g of the desired product.¹H NMR (300 MHz, DMSO d₆): δ 1.13 (s, 9H), 4.29 (d, J=5.4 Hz, 2H), 7.36(d, J=8.7 Hz, 1H), 7.45 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.4Hz, 2H), 8.06 (d, J=8.4 Hz, 2H), 8.19 (m, 1H), 12.79 (s, 1H); MS (m/z):456.59 (M+H)⁺.

Example-146N-(4-Chloro-3-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-83 by using 3-fluoro-4-(trifluoromethyl)benzoyl isocyanate(Intermediate-99, 2.0 g), tert-butyl2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate(Intermediate-94, 1.0 g), DCM (15 mL), and trifluoro acetic acid (3.0mL) to afford 0.900 g of the desired product. ¹H NMR (300 MHz, DMSO d₆):δ 1.12 (s, 9H), 4.29 (d, J=5.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.44 (s,1H), 7.62 (d, J=8.7 Hz, 1H), 7.86-8.10 (m, 3H), 8.19 (m, 1H), 12.86 (s,1H); MS (m/z): 471.35 (M+H)⁺.

Example-147N-(4-Chloro-3-(3-(4-chloro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-83 by using 4-chloro-3-(trifluoromethyl)benzoyl isocyanate(Intermediate-100, 2.0 g), tert-butyl2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate(Intermediate-94, 1.0 g), DCM (15 mL), and trifluoro acetic acid (3.0mL) to afford 0.900 g of the desired product. ¹H NMR (300 MHz, DMSO d₆):δ 1.12 (s, 9H), 4.29 (d, J=5.1 Hz, 2H), 7.36 (d, J=9.3 Hz, 1H), 7.43 (s,1H), 7.61 (d, J=8.4 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 8.10-8.18 (m, 2H),8.27 (s, 1H), 12.82 (s, 1H); MS (m/z): 487.29 (M+H)⁺.

Example-148N-(4-Chloro-3-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-83 by using 4-fluoro-3-(trifluoromethyl)benzoyl isocyanate(Intermediate-101, 0.196 g, 0.84 mmol), tert-butyl2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate(Intermediate-94, 0.150 g, 0.420 mmol), DCM (15 mL), and trifluoroacetic acid (3.0 mL) to afford 0.090 g of the desired product. ¹H NMR(300 MHz, DMSO d₆): δ 1.12 (s, 9H), 4.29 (d, J=5.7 Hz, 2H), 7.35 (d,J=8.4 Hz, 1H), 7.43 (s, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.70-7.76 (m, 1H),8.19-8.23 (m, 3H), 12.76 (s, 1H); MS (m/z): 471.32 (M+H)⁺.

Example-149N-(4-Chloro-3-(3-(3-fluoro-4-(3,3-dimethylbut-1-ynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide

Step 1:—Preparation ofN-(4-chloro-3-(3-(3-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide

The title compound was prepared according to the procedure described inExample-83 by using 3-fluoro-4-iodobenzoyl isocyanate (Intermediate-102,1.0 g), tert-butyl2-(2-chloro-5-{[(2-methylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate(Intermediate-97, 0.800 g), DCM (15 mL), and trifluoro acetic acid (3.0mL) to afford 0.900 g of the desired product. ¹H NMR (300 MHz, DMSO d₆):δ 1.30 (s, 6H), 2.43-2.45 (m, 1H), 4.26 (m, 2H), 7.01 (m, 1H), 7.46-7.49(m, 1H), 7.63-7.66 (m, 1H), 7.84-7.91 (m, 1H), 8.01-8.06 (m, 1H), 8.22(s, 1H), 8.36 (br s, 1H), 12.66 (m, 1H); MS (m/z): 515.21 (M+H)⁺.

Step-2:—Preparation ofN-(4-chloro-3-(3-(3-fluoro-4-(3,3-dimethylbut-1-ynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide

The title compound was prepared according to the procedure described inExample-111 by usingN-(4-chloro-3-(3-(3-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide(0.080 g, 0.155 mmol), 3,3-dimethylbut-1-yne (0.019 g, 0.233 mmol), TBAF(0.121 g, 0.466 mmol), bis(triphenylphosphine)palladium(II)chloride(0.004 g, 0.006 mmol) and DMSO (3.0 mL) to afford 0.009 g of the desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 1.02 (d, J=6.9 Hz, 6H), 1.31 (s,9H), 2.39-2.42 (m, 1H), 4.29 (d, J=5.7 Hz, 2H), 7.35 (d, J=7.5 Hz, 1H),7.43 (s, 1H), 7.57-7.67 (m, 4H), 8.37 (m, 1H), 13.0 (br s, 1H); MS(m/z): 469.31 (M+H)⁺.

Example-150N-(4-Chloro-3-(3-(4-(2-cyclopropylethynyl)-3-fluorophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide

The title compound was prepared according to the procedure described inExample-111 by usingN-(4-chloro-3-(3-(3-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide(step 1 of Example-149, 0.080 g, 0.155 mmol), ethynylcyclopropane (0.019g, 0.233 mmol), TBAF (0.121 g, 0.466 mmol),bis(triphenylphosphine)palladium(II)chloride (0.004 g, 0.006 mmol) andDMSO (3.0 mL) to afford 0.009 g of the desired product. ¹H NMR (300 MHz,DMSO d₆): δ 0.79-0.92 (m, 2H), 1.011 (m, 2H), 1.30 (s, 6H), 1.63 (m,1H), 2.39 (m, 1H), 4.28 (d, J=5.7 Hz, 2H), 7.35 (m, 1H), 7.43 (s, 1H),7.57-7.67 (m, 4H), 8.37 (m, 1H); MS (m/z): 453.24 (M+H)⁺.

Example-151N-(4-Chloro-3-(4,5-dihydro-5-oxo-3-(4-((pyrrolidin-1-yl)methyl)phenyl)-1,2,4-triazol-1-yl)benzyl)pivalamide

To a cold solution of pyrrolidine (0.060 g, 0.830 mmol) in DMF was addedNaH (0.034 g, 0.830 mmol) at 0° C. and stirred the reaction mass for 1h. Then solution ofN-(3-(3-(4-(bromomethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-4-chlorobenzyl)pivalamide(Intermediate-103, 0.200 g, 0.419) in DMF was added at 0° C. andcontinued stirring at 5-10° C. for 2-3 h. The reaction mass was quenchedin ice and pH adjusted to 6-7 and extracted with DCM. The organic layerwas dried over anhydrous sodium sulphate and concentrated. The obtainedcrude product was purified by column chromatography on basic alumina,eluting with 5% MeOH:DCM to afford 0.020 g of the desired product. ¹HNMR (300 MHz, DMSO d₆): δ 1.23 (s, 9H), 1.79 (br s, 4H), 2.53 (br s,4H), 3.66 (s, 2H), 4.48 (d, J=5.7 Hz, 2H), 6.08 (m, 1H), 7.26-7.54 (m,5H), 7.79 (d, J=7.8 Hz, 2H); MS (m/z): 468.51 (M+H)⁺.

Example-152N-(3-(3-(4-((2,2,2-Trifluoroethoxy)methyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-4-chlorobenzyl)pivalamide

To a solution of 2,2,2-trifloro ethanol (0.042 g, 0.410 mmol) in THF wasadded NaH (0.017 g, 0.041 mmol) at 10° C. and continued stirring at RTfor 1 h. Then solution ofN-(3-(3-(4-(bromomethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-4-chlorobenzyl)pivalamide(Intermediate-103, 0.100 g, 0.041 mmol) in THF and TBAI (0.004 g, 0.0012mmol) were added to the reaction mixture. The reaction mass was refluxedfor 2-3 h. The reaction mass was quenched in ice and pH adjusted to 6-7and extracted with DCM. The organic layer was dried over anhydroussodium sulphate and concentrated to afford 0.060 g of desired product.¹H NMR (300 MHz, DMSO d₆): δ 1.12 (s, 9H), 4.11-4.17 (m, 2H), 4.28 (d,J=5.4 Hz, 2H), 4.71 (s, 2H), 7.28 (d, J=9.0 Hz, 1H), 7.41 (s, 1H), 7.46(d, J=7.8 Hz, 2H), 7.57 (d, J=8.1 Hz, 1H), 7.85 (d, J=8.1 Hz, 2H), 8.18(t, 1H); MS (m/z): 497.31 (M+H)⁺.

Example-153N-(4-Chloro-3-(4,5-dihydro-3-(4-(5-isopropyl-1,3,4-oxadiazol-2-yl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-83 by using 4-(5-isopropyl-1,3,4-oxadiazol-2-yl)benzoylisocyanate (Intermediate-104, 0.196 g, 0.84 mmol), tert-butyl2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate(Intermediate-94, 0.150 g, 0.420 mmol), DCM (15 mL), and trifluoroacetic acid (3.0 mL) to afford 0.090 g of the desired product. ¹H NMR(300 MHz, DMSO d₆): δ 1.06 (s, 9H), 1.35 (s, 6H), 3.25 (m, 1H), 4.27 (d,J=5.4 Hz, 2H), 7.34 (d, J=8.1 Hz, 1H), 7.44 (s, 1H), 7.59 (d, J=8.4 Hz,1H), 8.01-8.04 (m, 2H), 8.10-8.17 (m, 3H), 12.73 (s, 1H); MS (m/z):495.39 (M+H)⁺.

Example-154N-(4-Chloro-3-(1-(4-chloro-3-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chlorophenyl)-2-(4-chloro-3-methylphenyl)-2H-1,2,4-triazol-3(4H)-one(Intermediate-106, 0.300 g, 0.859 mmol), pivaloyl chloride (0.130 g,1.03 mmol), TEA (2.0 mL), dry THF (5 mL) to afford 0.140 g of thedesired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.13 (s, 9H), 2.37 (s,3H), 4.29 (d, J=5.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.7 Hz,1H), 7.58 (s, 2H), 7.70 (br d, 1H), 7.91 (s, 1H), 8.20 (d, J=6.0 Hz,1H), 12.56 (s, 1H); MS (m/z): 433.38 (M+H)⁺.

Example-155 to Example-163 were prepared by following the proceduredescribed in Example-108 by using corresponding intermediates mentionedin table below, TEA and THF.

Intermediates Example No. and Example chemical name and characterizationused Structure data Intermediate- 106 + Isobutyryl chloride Example-155 

N-(4-Chloro-3-(1-(4-chloro-3-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3- yl)benzyl)isobutyramide. ¹H NMR(300 MHz, DMSO d₆): δ 1.02 (s, 3H), 1.05 (s, 3H), 2.38 (s, 3H), 4.29 (d,J = 6.0 Hz, 2H), 7.42 (d, J = 9.0 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H),7.60 (s, 2H), 7.82 (br d, 1H), 7.91 (s, 1H), 8.38 (t, 1H), 12.57 (s,1H); MS (m/z): 433.30 (M + H)⁺. Intermediate- 130 + Pivaloyl chlorideExample-156  

N-(4-Chloro-3-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide. ¹H NMR (300 MHz, DMSO d₆): δ1.13 (s, 9H), 4.30 (d, J = 6.3 Hz, 2H), 7.42 (d, J = 8.40 Hz, 1H), 7.61(m, 3H), 8.09 (d, 1H), 8.14 (s, 1H), 8.20 (t, 1H), 12.80 (s, 1H); MS(m/z): 471.39 (M + H)⁺. Intermediate- 131 + Pivaloyl chlorideExample-157  

N-(4-Chloro-3-(1-(4-chloro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide. ¹H NMR (300 MHz, DMSO-d₆): δ1.13 (s, 9H), 4.30 (d, J = 6.0 Hz, 2H), 7.42 (d, J = 7.20 Hz, 1H), 7.62(d, J = 8.10 Hz, 2H), 7.86 (d, J = 8.7 Hz, 1H), 8.19-8.26 (m, 2H), 8.42(s, 1H), 12.76 (s, 1H); MS (m/z): 487.43 (M + H)⁺. Intermediate- 133 +Pivaloyl chloride Example-158  

N-(4-Chloro-3-(1-(3-(trifluoromethyl)-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide. ¹H NMR (300 MHz, DMSO d₆): δ 1.13 (s,9H), 2.46 (s, 3H), 4.31 (d, J = 5.7 Hz, 2H), 7.39 (d, J = 7.8 Hz, 2H),7.57 (d, 2H), 7.68 (d, 2H), 7.80 (s, 1H), 12.47 (s, 1H); MS (m/z):467.22 (M + H)⁺. Intermediate- 134 + Pivaloyl chloride Example-159  

N-(4-Chloro-3-(1-(4-(trifluoromethyl)-2-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide. ¹H NMR (300 MHz, DMSO d₆): δ 1.12 (s,9H), 2.39 (s, 3H), 4.28 (d, 2H), 7.43 (d, 1H), 7.55-7.60 (m, 3H), 8.12(d, 1H), 8.20 (m, 1H), 8.29 (s, 1H), 12.65 (s, 1H); MS (m/z): 467.15(M + H)⁺. Intermediate- 135 + Pivaloyl chloride Example-160  

N-(4-Chloro-3-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide. ¹H NMR (300 MHz, DMSO d₆): δ1.13 (s, 9H), 4.29 (d, J = 4.8 Hz, 2H), 7.43 (m, 1H), 7.60- 7.61 (m,2H), 7.91-7.94 (m, 1H), 7.98-8.06 (m, 2H), 8.19 (t, 1H); MS (m/z):471.18 (M + H)⁺. Intermediate- 135 + Isobutyryl chloride Example-161  

N-(4-Chloro-3-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)isobutyramide. ¹H NMR (300 MHz, DMSO d₆): δ1.02 (s, 3H), 1.05 (s, 3H), 2.43 (m, 1H), 4.29 (d, J = 6.6 Hz, 2H), 7.42(d, J = 7.5 Hz, 1H), 7.60 (s, 1H), 7.63 (br s, 1H), 7.91 (t, J = 6.9 Hz,1H), 7.99-8.08 (m, 2H), 8.40 (t, 1H); MS (m/z): 455.01 (M + H)⁺.Intermediate- 63 + Isopropyl sulfonyl chloride Example-162  

N-(4-Chloro-3-{5-oxo-1-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}benzyl)propane-2-sulfonamide. ¹H NMR (300 MHz, DMSO d₆): δ1.22 (s, 3H), 1.24 (s, 3H), 3.17 (m, 1H), 4.23 (d, J = 6.0 Hz, 2H), 7.56(d, J = 7.8 Hz, 1H), 7.65-7.72 (m, 3H), 7.87 (d, J = 8.4 Hz, 2H), 8.19(d, J = 8.7 Hz 2H), 12.72 (s, 1H); MS (m/z): 475.15 (M + H)⁺.Intermediate- 136 + Pivaloyl chloride Example-163  

N-(4-Chloro-3-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide. ¹H NMR (300 MHz, DMSO d₆): δ1.12 (s, 9H), 7.28 (d, J = 5.7 Hz, 2H), 7.40 (d, J = 7.8 Hz, 1H),7.57-7.62 (m, 2H), 7.75 (d, J = 7.8 Hz, 1H), 7.90-7.98 (m, 2H), 8.18 (t,1H), 12.59 (s, 1H); MS (m/z): 471.17 (M + H)⁺.

Example-164 to Example-171 were prepared by following the proceduredescribed in Example-111 by using corresponding intermediates mentionedin table below, bis(triphenylphosphine)palladium(II) chloride, TBAF andDMSO.

Intermediates Example No. and Example chemical name and used StructureCharacterization data Intermediate- 140 + 3,3- dimethylbut-1- yneExample 164  

N-(3-(4,5-Dihydro-1-(4-(3,3-dimethylbut-1-ynyl)phenyl)-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)isobutyramide. ¹H NMR (300 MHz, DMSO d₆): δ 1.01(s, 3H), 1.04 (s, 3H), 1.26 (s, 9H), 2.16 (s, 3H), 2.20 (s, 3H), 2.42(m, 1H), 4.24 (d, J = 6.3 Hz, 2H), 7.17 (d, J = 7.8 Hz, 1H), 7.27 (d, J= 8.4 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H), 8.19(t, 1H), 12.23 (s, 1H); MS (m/z): 445.26 (M + H)⁺. Intermediate- 138 +Ethynyl- cyclopropane Example 165  

N-(3-(1-(4-(2-Cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)- 2,4-dimethylbenzyl)pivalamide.¹H NMR (300 MHz, DMSO d₆): δ 0.73 (m, 2H), 0.88 (m, 2H), 1.14 (s, 9H),1.54 (s, 3H), 2.16 (s, 3H), 2.19 (s, 3H), 4.23 (d, J = 6.0 Hz, 2H), 7.16(d, J = 8.4 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H),7.91 (d, J = 9.0 Hz, 2H), 8.00 (t, 1H), 12.22 (s, 1H); MS (m/z): 443.51(M + H)⁺. Intermediate- 119 + Ethynyl- cyclopropane Example 166  

N-(4-Chloro-3-(3-(4-(2- cyclopropylethynyl)-3-fluorophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1- yl)benzyl)pivalamide. ¹H NMR (300 MHz,DMSO d₆): δ 0.80 (m, 2H), 0.93-0.95 (m, 2H), 1.12 (s, 9H), 1.63 (m, 1H),4.28 (d, J = 6.3 Hz, 2H), 7.35 (d, J = 9.0 Hz, 1H), 7.43 (s, 1H),7.59-7.67 (m, 4H), 8.19 (t, 1H), 12.66 (s, 1H); MS (m/z): 467.24 (M +H)⁺. Intermediate- 139 + Ethynyl- cyclopropane Example 167  

N-(4-Chloro-3-(1-(4-(2- cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3- yl)benzyl)pivalamide. ¹H NMR (300 MHz, DMSO d₆):δ 0.73 (m, 2H), 0.89 (m, 2H), 1.13 (s, 9H), 1.54 (m, 1H), 4.30 (d, 2H),7.41-7.47 (m, 2H), 7.58 (s, 2H), 7.81 (m, 1H), 7.91 (d, J = 6.3 Hz, 2H),8.18 (br s, 1H), 12.56 (s, 1H); MS (m/z): 449.30 (M + H)⁺. Intermediate-124 + Ethynyl- cyclopropane Example 168  

N-(4-Chloro-3-(3-(4-(2- cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1- yl)benzyl)pivalamide. ¹H NMR (300 MHz,DMSO d₆): δ 0.78 (m, 2H), 0.93 (m, 2H), 1.12 (s, 9H), 1.59 (m, 1H), 4.28(d, J = 6.6 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.41 (m, 2H), 7.62 (d, J= 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 8.19 (t, 1H), 12.40 (s, 1H); MS(m/z): 467.20 (M)⁺. Intermediate- 143 + Ethynyl- cyclopropane Example169  

N-(3-(1-(4-(2-Cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)-3-fluoro-2,2- dimethylpropanamide. ¹H NMR (300 MHz,DMSO d₆): δ 0.74 (m, 2H), 0.85 (m, 2H), 1.15 (s, 6H), 1.54 (m, 1H), 2.15(s, 3H), 2.19 (s, 3H), 4.27 (d, 2H), 4.43 (s, 1H), 4.49 (s, 1H),7.17-7.24 (m, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.7 Hz, 2H),8.16 (s, 1H), 12.22 (s, 1H); MS (m/z): 461.21 (M + H)⁺. Intermediate-141 + 3,3- dimethylbut-1- yne Example 170  

N-(3-(1-(3-Fluoro-4-(3,3-dimethylbut-1-ynyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4- triazol-3-yl)-2,4-dimethylbenzyl)isobutyramide. ¹H NMR (300 MHz, DMSO d₆): δ 1.01 (s, 3H),1.04 (s, 3H), 1.23 (s, 9H), 2.15 (s, 3H), 2.20 (s, 3H), 4.25 (d, 2H),7.18 (m, 1H), 7.26 (m, 1H), 7.51 (m, 1H), 7.84 (m, 2H), 8.19 (t, 1H),12.35 (s, 1H); MS (m/z): 463.151 (M + H)⁺. Intermediate- 45 +1,4-dichloro-2- ethynylbenzene Example 171  

2-(2,6-Dichlorophenyl)-5-(4-(2-(2,5- dichlorophenyl)ethynyl)-3-methoxyphenyl)-2H -1,2,4-triazol-3(4H)- one. ¹H NMR (300 MHz, DMSO d₆):δ 3.92 (s, 3H), 7.54 (m, 4H), 7.58-7.69 (m, 4H), 7.75 (s, 1H), 12-13 (brs, 1H); MS (m/z): 506.01 (M + H)⁺.

Example-172 was prepared by following the procedure described inIntermediate-41 by using corresponding intermediates mentioned in tablebelow, NaH and DMF.

Intermediate Example No. and Example chemical name and characterizationused Structure data Intermediate- 103 + 3,5-dimethyl- 1H-pyrazoleExample-172  

N-(4-Chloro-3-(4,5-dihydro-3-(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide. ¹H NMR (300 MHz, DMSO d₆): δ1.11 (s, 9H), 2.10 (s, 3H), 2.15 (s, 3H), 4.28 (d, J = 5.1 Hz, 2H), 5.24(s, 2H), 5.87 (s, 1H), 7.19 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 8.7 Hz,1H), 7.22 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H),8.18 (t, 1H); MS (m/z): 493.36 (M)⁺.

Example-173 and Example-174 were prepared by following the procedure asdescribed in Example-83 by using corresponding intermediates mentionedin table below, TFA and DCM.

Intermediates Example No. and Example chemical name and characterizationused Structure data Intermediate- 109 + Intermediate- 51 Example-173  

N-(4-Chloro-2-fluoro-3-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide. ¹H NMR (300 MHz, CDCl₃): δ 1.21(s, 9H), 4.46 (d, J = 5.7 Hz, 2H), 6.21 (t, 1H), 6.42 (d, 1H), 7.32 (s,1H), 7.42 (t, 1H), 7.65 (t, 1H), 7.96 (m, 2H); MS (m/z): 489.56 (M)⁺.Intermediate- 111 + Intermediate- 51 Example-174  

N-(4-Chloro-3-(1-(4-chloro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide. ¹H NMR (300 MHz, DMSOd₆): δ 1.13 (s, 9H), 430 (d, J = 6.0 Hz, 2H), 7.46 (d, J = 7.8 Hz, 1H),7.55 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 8.20 (t, 2H), 8.41(s, 1H), 12.90 (m, 1H); MS (m/z): 505.27 (M + H)⁺.

Example-175 was prepared by following the procedure as described indescribed for step-2 of Example-134 by using Example-115, DAST and THF.

Intermediates Example No. and Example chemical name and characterizationused Structure data Example-115 Example-175  

N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4.5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-3-fluoro-2,2-dimethylpropanamide. ¹H NMR (300 MHz, DMSO d₆):δ 1.15 (s, 6H), 4.33 (m, 4H), 7.41 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 7.8Hz, 2H), 7.85 (d, J = 9.3 Hz, 2H), 8.20 (d, J = 8.4 Hz, 2H), 8.35 (t,1H), 12.71 (m, 1H); MS (m/z): 471.28 (M + H)⁺.

Example-176 to Example-179 were prepared by following the procedure asdescribed for step-6 of Intermediate-26 by using correspondingintermediates used mentioned in table below, trimethyl aluminium (2Msolution in toluene) and dry toluene.

Intermediates Example chemical name and characterization used ExampleNo. and Structure data Step-5 of Intermediate- 45 + methyl 4-(trifluoromethyl) benzoate Example-176  

N-(4-(1-(2,6-Dichlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazo1-3-yl)-2- methoxyphenyl)-4-(trifluoromethyl)benzamide. ¹H NMR (300 MHz, DMSO d₆): δ 3.91 (s, 3H),7.49-7.64 (m, 3H), 7.72.-7.74 (m, 2H), 7.91 (d, J = 8.4 Hz, 2H), 7.98(d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.1 Hz, 2H), 9.90 (s, 1H), 12.70 (s,1H); MS (m/z): 523.10 (M + H)⁺. Step-5 of Intermediate- 45 + methyl 3,5-difluorobenzoate Example-177  

N-(4-(1-(2,6-Dichlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-3,5-difluorobenzamide. ¹H NMR (300 MHz, DMSO d₆): δ 3.90(s, 3H), 7.47-7.61 (m, 4H), 7.64.-7.72 (m, 4H), 7.88 (d, J = 7.8 Hz,1H), 9.86 (s, 1H), 12.69 (s, 1H); MS (m/z): 491.03 (M + H)⁺.Intermediate- 46 + 2-fluoro-5- (trifluoromethyl) aniline Example-178  

4-(1-(2,6-Dichlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-N-(2- fluoro-5-(trifluoromethyl)phenyl)-2-methoxybenzamide. ¹H NMR (300 MHz, DMSO d₆): δ 4.06 (s, 3H), 7.60- 7.65(m, 5H), 7.55.-7.67 (m, 2H), 8.03 (d, J = 7.8 Hz, 1H), 8.60 (s, 1H),10.44 (s, 1H), 12.90 (s, 1H); MS (m/z): 541.05 (M + H)⁺. Intermediate-46 + 2-chloro-4- methyl aniline Example-179  

N-(2-Chloro-4-methylphenyl)-4-(1-(2,6-dichlorophenyl)-4,5-dihydro-5-oxo-1H- 1,2,4-triazol-3-yl)-2-methoxybenzamide. ¹H NMR (300 MHz, DMSO d₆): δ 2.30 (s, 3H), 4.13 (s,3H), 7.20 (d, J = 8.7 Hz, 1H), 7.41 (s, 1H), 7.41-7.75 (m, 5H), 8.15 (d,J = 7.8 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 10.47 (s, 1H), 12.91 (s, 1H);MS (m/z): 503.00 (M + H)⁺.

Example-180N-((6-Cyclopropyl-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)pivalamide

Step-1:—Preparation of tert-butyl(6-cyclopropyl-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methylcarbamate

A solution of6-cyclopropyl-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridine-3-carbonitrile(0.110 g) in ethanol (10 mL) and BOC anhydride (0.150 g), TEA (1.0 mL),Pd/C (catalytic amount) was stirred under hydrogen atmosphere under35-40 psi pressure in Parr apparatus for 4-5 h. The reaction mass wasfiltered and the obtained filtrate was concentrated to afford 0.100 g ofdesired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.93-0.98 (m, 4H), 1.36(s, 9H), 2.09 (m, 1H), 4.12 (d, J=5.7 Hz, 2H), 7.51 (m, 1H), 7.69 (s,1H), 7.88 (d, J=8.4 Hz, 2H), 8.43 (d, J=7.8 Hz, 2H); MS (m/z): 476.13(M+H)⁺.

Step-2:—PreparationN-((6-cyclopropyl-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)pivalamide

Stirred a solution of tert-butyl(6-cyclopropyl-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methylcarbamate(0.100 g) in EtOC:HCl (5.0 mL) for 6 h at RT. Excess of solvent wasremoved and added DCM (5.0 mL), TEA (0.5 mL) and pivaloyl chloride(0.045 g) under nitrogen atmosphere o the reaction mixture. The reactionmass was stirred at RT for 4 h. Excess of solvent was removed undervacuum and the residue was diluted with water, extracted with EtOAC andconcentrated to afford 0.020 g of the product. ¹H NMR (300 MHz, DMSOd₆): δ 0.98 (m, 4H), 1.12 (s, 9H), 2.73 (m, 1H), 4.27 (d, J=6.0 Hz, 2H),7.78 (s, 1H), 7.85 (d, J=8.7 Hz, 2H), 8.13 (t, 1H), 8.19 (d, J=9.3 Hz,2H), 8.40 (s, 1H), 12.75 (s, 1H); MS (m/z): 460.30 (M+H)⁺

Example-181N-(4-Chloro-3-(1-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

Step 1:—Preparation ofN-(4-chloro-3-(1-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample-111 by usingN-(4-chloro-3-(1-(2-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(Intermediate-126, 1.100 g, 3.88 mmol), ethynylcyclopropane (0.127 g,1.93 mmol), TBAF (1.10 g, 3.88 mmol),bis(triphenylphosphine)palladium(II) chloride (0.036 g, 0.051 mmol) andDMSO (3.0 mL) to afford 0.400 g of the desired title product. ¹H NMR(400 MHz, DMSO d₆): δ 0.95 (m, 4H), 1.56 (m, 1H), 4.44 (br s, 2H), 7.32(d, J=7.8 Hz, 1H), 7.42-7.46 (m, 2H), 7.58 (t, J=7.8 Hz, 1H), 7.65 (m,3H), 10.12 (br s, 1H); MS (m/z): 479.11 (M+H)⁺.

Step 2:—Preparation of5-(5-(aminomethyl)-2-chlorophenyl)-2-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one

The title compound was prepared by following the procedure as describedin step-2 of Intermediate-106 by usingN-(4-chloro-3-(1-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(0.300 g), KOH (0.300 g), water (2.0 mL), THF (10.0 mL) to afford 0.200g of desired product. MS (m/z): 383.16 (M+H)⁺.

Step-3:—Preparation ofN-(4-chloro-3-(1-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

The title compound was prepared according to the procedure described inExample-108 by using5-(5-(aminomethyl)-2-chlorophenyl)-2-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one(0.100 g, 0.266 mmol), pivaloyl chloride (0.040 g, 0.319 mmol), THF(10.0 mL) and TEA (2 mL) to afford 0.040 g of the desired product. ¹HNMR (400 MHz, DMSO d₆): δ 0.78 (m, 2H), 0.919 (m, 2H), 1.11 (br s, 9H),1.56 (m, 1H), 4.28 (br d, 2H), 7.32-7.41 (m, 3H), 7.56 (br s, 3H), 8.16(s, 1H), 12.46 (s, 1H); MS (m/z): 467.22 (M+H)⁺.

Example-182N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2-methylpropane-2-sulfonamide

To a solution ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2-methylpropane-2-sulfinamide(Intermediate-144, 0.075 g, 0.158 mmol) in mixture ofDCM:acetonitrile:water (0.2 ml:0.2 mL:0.3 mL), sodium periodate (0.050g, 0.238 mmol) and ruthenium chloride (0.001 g, 0.003 mmol) were addedand the reaction mass was stirred at RT for 4 h. After completion of thereaction the reaction mass was filtered through celite bed and extractedwith DCM. The organic layer was separated, dried over anhydrous sodiumsulphate and concentrated. The obtained product was purified with columnchromatography on neutral alumina eluting with 10% MeOH:DCM to afford0.020 g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.30 (s,9H), 4.31 (d, J=6.0 Hz, 2H), 7.55-7.71 (m, 4H), 7.86 (d, J=8.7 Hz, 2H),8.19 (d, J=9.0 Hz, 2H), 12.71 (s, 1H). MS (m/z): 489.04 (M+H)⁺.

Example-1836-(Difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)nicotinonitrile

The title compound was prepared by following the procedure as describedin Example-83 by using 5-cyano-2-(difluoromethyl)nicotinoyl isocyanate(Intermediate-145, 0.900 g, 4.03 mmol), tert-butyl2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 1.0g, 3.63 mmol), TFA (10 mL), DCM (40 mL) to afford 0.350 g of the desiredproduct. ¹H NMR (300 MHz, DMSO d₆): δ 7.45-7.56 (t, J=53.4 Hz, 1H), 7.90(d, J=9.3 Hz, 2H), 8.20 (d, J=8.7 Hz, 2H), 8.77 (s, 1H), 9.32 (s, 1H),13.01 (s, 1H); MS (m/z): 382.15 (M+H)⁺.

Example-184N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclobutanecarboxamide

The title compound was prepared according to the procedure described inExample-108 by using3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-63, 0.100 g, 0.271 mmol), TEA (1.0 mL), DCM (10 mL),cyclobutanecarbonyl chloride (0.041 g, 0.352 mmol) to afford 0.020 g ofthe desired product. ¹H NMR (300 MHz, DMSO d₆): δ 2.05 (m, 6H), 3.08 (m,1H), 4.29 (m, 2H), 7.44 (m, 1H), 7.60 (m, 2H), 7.86 (m, 2H), 8.17 (m,3H), 12.69 (s, 1H); MS (m/z): 451.07 (M+H)⁺.

Example-185N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopentanecarboxamide

The title compound was prepared according to the procedure described inExample-17 by using3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(Intermediate-63, 0.100 g, 0.271 mmol), TEA (1.0 mL), TBTU (0.261 g,0.813 mmol), THF:DMF (10 mL), cyclopentanecarboxylic acid (0.061 g,0.542 mmol) to afford 0.025 g of the desired product. ¹H NMR (300 MHz,DMSO d₆): δ 1.50-1.76 (m, 8H), 2.62 (s, 1H), 4.30 (d, 2H), 7.45 (m, 1H),7.61 (m, 2H), 7.85 (d, J=9.6 Hz, 2H), 8.19 (d, J=8.1 Hz, 2H), 8.40 (m,1H), 12.69 (s, 1H); MS (m/z): 465.08 (M+H)⁺.

Example-186N-((6-(Difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)pivalamide

Step-1:—Preparation of3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared according to the procedure described inIntermediate-16 by using6-(difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)nicotinonitrile(Example-183, 0.050 g, 0.13 mmol), Raney Ni (catalytic amount), TEA(0.040 g, 0.39 mmol) in ethanol (20 mL) to afford 0.50 g of the desiredproduct.

Step-2:—Preparation ofN-((6-(difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)pivalamide

The title compound was prepared by following the procedure as describedin Example-108 by using3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(0.50 g, 0.12 mmol), pivaloyl chloride (0.018 g, 0.14 mmol), TEA (0.038g, 0.37 mmol) in DCM (10 mL) to afford 0.010 g of the desired product.¹H NMR (300 MHz, DMSO d₆): δ 1.18 (s, 9H), 4.38 (s, 2H), 7.24-7.63 (m,1H), 7.64 (d, J=8.4 Hz, 2H), 7.99 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 8.61(s, 1H); MS (m/z): 470.25 (M+H)⁺.

Example-187N-((6-(Difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)isobutyramide

The title compound was prepared by following the procedure as describedin Example-108 by using3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(step-1 of Example-186, 0.50 g, 0.12 mmol), isobutyryl chloride (0.017g, 0.15 mmol), TEA (0.042 g, 0.41 mmol) and DCM (10 mL) to afford 0.015g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.14-1.21 (m,6H), 2.47 (m, 1H), 4.47 (s, 2H), 7.32-7.54 (m, 1H), 7.72 (d, J=8.7 Hz,2H), 8.09 (br s, 1H), 8.18 (d, J=7.8 Hz, 2H), 8.70 (s, 1H); MS (m/z):456.14 (M+H)⁺.

Example-188N-((6-(Difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)propane-2-sulfonamide

The title compound was prepared by following the procedure as describedin Example-108 by using3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(step-1 of Example-186, 0.75 g, 0.19 mmol), isopropyl sulphonyl chloride(0.042 g, 0.29 mmol), TEA (0.059 g, 0.58 mmol), and DCM (10 mL) toafford 0.012 g of desired product. ¹H NMR (300 MHz, DMSO d₆): δ 1.32 (s,3H), 1.35 (s, 3H), 3.15 (m, 1H), 4.36 (s, 2H), 7.26-7.66 (m, 3H),8.08-8.11 (m, 3H), 8.65 (s, 1H); MS (m/z): 492.08 (M+H)⁺.

Example-189N-((6-(Difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclobutanecarboxamide

The title compound was prepared by following the procedure as describedin Example-108 by using3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(step-1 of Example-186, 0.75 g, 0.19 mmol), cyclobutane carbonylchloride (0.035 g, 0.29 mmol), TEA (0.059 g, 0.58 mmol) and DCM (10 mL)to afford 0.020 g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ1.89-2.29 (m, 7H), 4.45 (s, 2H), 7.31-7.52 (m, 1H), 7.72 (d, J=8.4 Hz,2H), 8.05 (s, 1H), 8.18 (d, J=8.4 Hz, 2H), 8.66 (s, 1H); MS (m/z):468.26 (M+H)⁺.

Example-190N-(4-Chloro-3-(3-(4-(cyclopropylethynyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure described inExample 111 usingN-(4-chloro-3-(3-(4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide(Intermediate-146, 0.300 g, 0.568 mmol), ethynylcyclopropane (0.056 g,0.852 mmol), TBAF (0.444 g, 1.72 mmol),bis(triphenylphosphine)palladium(II) chloride (0.016 g, 0.022 mmol) andDMSO (3.0 mL) to afford 0.020 g of the desired product. ¹H NMR (300 MHz,DMSO d₆): δ 0.75 (m, 2H), 0.90 (m, 2H), 1.55 (m, 1H), 4.43 (d, J=6.0 Hz,2H), 7.38 (d, J=6.6 Hz, 1H), 7.46-7.51 (m, 3H), 7.64 (d, J=8.1 Hz, 1H),7.76 (d, J=8.4 Hz, 2H), 10.06 (m, 1H), 12-13 (br s, 1H). MS (m/z):461.12 (M+H)⁺.

Example-191N-(4-Chloro-3-(3-(4-(cyclopropylethynyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-3-hydroxy-2,2-dimethylpropanamide

Step-1:—Preparation of1-(5-(aminomethyl)-2-chlorophenyl)-3-(4-(cyclopropylethynyl)phenyl)-1H-1,2,4-triazol-5(4H)-one

The title compound was prepared by following the procedure as describedin step-2 of Intermediate-106 by usingN-(4-chloro-3-(3-(4-(cyclopropylethynyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide(Example-190, 0.100 g), LiOH (0.100 g), water (2.0 mL), THF (10.0 mL) toafford 0.050 g of the desired product. MS (m/z): 365.83 (M+H)⁺.

Step-2:—Preparation ofN-(4-chloro-3-(3-(4-(cyclopropylethynyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-3-hydroxy-2,2-dimethylpropanamide

The title compound was prepared according to the procedure described inExample-107 by using1-(5-(aminomethyl)-2-chlorophenyl)-3-(4-(cyclopropylethynyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(0.080 g, 0.228 mmol), DMF (5 mL), 3-methoxy-2,2-dimethylpropanoic acid(0.040 g, 0.342 mmol), BOP (0.151 g, 0.342 mmol), TEA (2.0 mL) to afford0.010 g of the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.75 (m,2H), 0.83 (m, 2H), 1.10 (s, 6H), 1.51 (m, 1H), 3.34 (m 2H), 4.31 (br s,2H), 4.85 (m, 1H), 7.37-7.50 (m, 3H), 7.58 (d, J=7.8 Hz, 1H), 7.77-7.83(m, 3H), 8.11 (br s, 1H), 12.56 (s, 1H); MS (m/z): 465.07 (M+H)⁺.

Example-1923-Fluoro-N-((6-(difluoromethyl)-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)-2,2-dimethylpropanamide

Step-1:—Preparation ofN-((6-(difluoromethyl)-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)-3-hydroxy-2,2-dimethylpropanamide

The title compound was prepared by following the procedure as describedin Example-107 by using3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one(step-1 of Example-186, 0.130 g, 0.33 mmol), DMF (5 mL),3-methoxy-2,2-dimethylpropanoic acid (0.060 g, 0.50 mmol), BOP (0.224 g,0.50 mmol), TEA (2.0 mL) to afford 0.070 g of the desired product. MS(m/z): 486.22 (M+H)⁺.

Step-2:—Preparation of3-fluoro-N-((6-(difluoromethyl)-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)-2,2-dimethylpropanamide

The title compound was prepared by following the procedure as describedin step-2 of Example-134 by usingN-((6-(difluoromethyl)-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)-3-hydroxy-2,2-dimethylpropanamide(0.060 g, 0.12 mmol), DAST (0.060 g, 0.37 mmol), DCM (10 mL) to afford0.005 g the desired product. ¹H NMR (300 MHz, DMSO d₆): δ 0.80 (br s,6H), 4.22 (br s, 1H), 4.38-4.42 (m, 3H), 7.41-7.66 (m, 3H), 7.95 (br s,1H), 8.08-8.11 (m, 2H), 8.61 (s, 1H); MS (m/z): 488.23 (M+H)⁺.

Pharmacological Activity

In-Vitro Protocol for Screening of mPGES-1 Inhibitors:

mPGES-1 (Microsomal prostaglandin E synthase-1) is a microsomal enzymethat converts endoperoxide substrate PGH₂ (prostaglandin H₂) to productPGE₂ (prostaglandin E₂) by isomerization in the presence of reducedglutathione (GSH). mPGES-1 inhibitors were screened by assessing theirability to inhibit formation of PGE₂ from PGH₂ in the presence ofmPGES-1 using an anti-PGE₂ antibody based detection method. Recombinanthuman mPGES-1 was generated in-house by expression in CHO cells (OuelletM et al. (2002), Protein Expression and Purification 26: 489-495). Theassay was set up using crude microsomal fractions at a proteinconcentration of 40-60 μg/mL. Test compounds were prepared in 100%dimethyl sulfoxide (DMSO) to obtain 20 mM stock solution and thendiluted using assay buffer comprising 0.1 M Potassium phosphate bufferwith 2 mM EDTA. The final concentration of DMSO in the reaction was 0.5%(v/v). Negative controls were comprised of all assay reagents except theenzyme. Positive controls were comprised of the enzyme reaction in theabsence of any inhibitor. Test compounds were incubated for 10 minutesin assay buffer containing 2.5 mM GSH and mPGES-1 enzyme followed byaddition of PGH₂ at a concentration of 15 μM for 1 minute. The reactionwas stopped by addition of Stannous chloride (11 mg/ml) and PGE₂ levelswere measured (Masse F et al. (2005), Journal of Biomolecular Screening10(6) 599-605; Goedken R E et al. (2008), Journal of BiomolecularScreening 13 (7): 619-625) by HTRF kit (CisBio)).

Inhibition of mPGES-1 enzyme activity was measured using the percent ofreaction occurring in the positive control. Concentration responsecurves were plotted using percent inhibition of maximum enzyme reaction.The IC₅₀ value was calculated from the concentration response curve bynonlinear regression analysis using GraphPad PRISM software.

The compounds prepared were tested using the above assay procedure andthe results obtained are given in Table 1. Percentage inhibition atconcentrations of 1.0 μM, 3.0 μM or 10.0 μM are given in the table alongwith IC₅₀ (nM) details for selected examples. The compounds preparedwere tested using the above assay procedure and were found to have IC₅₀less than 200 nM, preferably less than 100 nM, more preferably less than50 nM or most preferably less than 20 nM.

The IC₅₀ (nM) values of some of the compounds are set forth in Table 1wherein “A” refers to an IC₅₀ value of less than 50 nM, “B” refers toIC₅₀ value in range of 50.01 to 100.0 nM and “C” refers to IC₅₀ valuesmore than 100 nM.

TABLE 1 Sr. Percentage inhibition at IC₅₀ No. Example No. 1 μM 3 μM 10μM (nM) 1. Example-1 9.32 — 68.18 — 2. Example-2 17.97 — 18.97 — 3.Example-3 88.90 96.79 — A 4. Example-4 46.43 — 69.70 — 5. Example-591.83 — 86.21 A 6. Example-6 83.89 — 87.67 A 7. Example-7 89.12 — 95.25A 8. Example-8 84.86 — 87.24 B 9. Example-9 1.53 — 23.19 — 10.Example-10 84.88 — 91.21 A 11. Example-11 2.34 — 71.72 — 12. Example-1284.76 — 87.54 A 13. Example-13 86.27 — 90.42 C 14. Example-14 95.99 —95.82 B 15. Example-15 64.15 — 83.79 — 16. Example-16 40.88 — 92.28 —17. Example-17 2.52 — 44.08 — 18. Example-18 56.23 — 98.10 — 19.Example-19 5.11 — 29.66 — 20. Example-20 22.37 — 87.36 — 21. Example-2176.06 — 91.78 — 22. Example-22 39.26 — 99.73 — 23. Example-23 13.25 —52.94 — 24. Example-24 70.96 — 83.09 — 25. Example-25 74.44 — 88.92 C26. Example-26 80.56 — 88.14 C 27. Example-27 72.84 — 97.54 — 28.Example-28 72.22 — 95.51 — 29. Example-29 79.21 — 85.78 C 30. Example-3089.60 — 94.52 A 31. Example-31 96.88 — 98.63 B 32. Example-32 88.85 —93.97 B 33. Example-33 89.42 — 96.78 A 34. Example-34 70.73 — 92.28 —35. Example-35 37.43 — 59.15 — 36. Example-36 97.34 — 98.90 A 37.Example-37 50.96 — 94.31 — 38. Example-38 87.36 — 84.91 B 39. Example-3990.06 — 96.37 B 40. Example-40 89.05 — 90.68 A 41. Example-41 58.81 —87.08 — 42. Example-42 96.55 — 99.65 A 43. Example-43 98.58 — 99.05 A44. Example-44 97.37 — 99.03 A 45. Example-45 81.65 — 90.11 A 46.Example-46 59.77 — 72.09 — 47. Example-47 89.46 — 96.51 A 48. Example-4898.33 — 100.00 A 49. Example-49 89.15 — 96.34 A 50. Example-50 95.32 —99.85 B 51. Example-51 88.29 — 85.96 A 52. Example-52 96.44 — 98.34 A53. Example-53 82.70 — 97.89 A 54. Example-54 89.36 — 97.50 B 55.Example-55 80.95 91.85 — A 56. Example-56 98.08 — 98.54 A 57. Example-5798.73 98.55 — A 58. Example-58 95.20 — 97.32 B 59. Example-59 93.91 —96.80 A 60. Example-60 95.39 — 93.07 A 61. Example-61 92.44 — 96.85 A62. Example-62 97.77 — 98.29 A 63. Example-63 92.41 — 94.79 A 64.Example-64 28.94 — 63.78 — 65. Example-65 75.45 — 94.48 — 66. Example-6687.85 — 98.83 C 67. Example-67 72.71 — 96.32 — 68. Example-68 97.39 —96.41 A 69. Example-69 86.44 — 89.11 C 70. Example-70 0.55 — 6.63 — 71.Example-71 12.95 — 17.88 — 72. Example-72 99.24 99.05 — A 73. Example-7392.38 — 92.43 A 74. Example-74 93.25 — 98.71 B 75. Example-75 99.07 —98.31 A 76. Example-76 95.62 — 95.38 A 77. Example-77 93.21 — 98.06 B78. Example-78 99.94 — 99.88 A 79. Example-79 99.14 — 97.14 A 80.Example-80 96.99 — 97.10 A 81. Example-81 99.76 — 98.05 A 82. Example-8298.26 — 98.96 A 83. Example-83 97.49 — 99.86 A 84. Example-84 98.81 —99.51 A 85. Example-85 22.58 — 69.28 — 86. Example-86 79.87 — 96.68 C87. Example-87 93.36 — 99.19 B 88. Example-88 3.34 — 39.18 — 89.Example-89 95.30 — 99.06 A 90. Example-90 81.74 — 97.20 C 91. Example-9166.15 — 94.31 — 92. Example-92 76.02 — 99.37 C 93. Example-93 96.83 —99.60 A 94. Example-94 87.02 — 100.00 C 95. Example-95 98.71 — 99.04 A96. Example-96 52.25 — 68.70 — 97. Example-97 20.19 — 6.88 — 98.Example-98 97.52 — 99.45 A 99. Example-99 95.30 — 98.55 A 100.Example-100 99.97 — 98.56 A 101. Example-101 94.97 — 98.18 A 102.Example-102 96.52 — 98.03 A 103. Example-103 19.92 — 51.12 — 104.Example-104 96.91 — 99.50 A 105. Example-105 73.88 — 95.96 C 106.Example-106 92.03 — 96.77 C 107. Example-107 56.07 — 90.50 — 108.Example-108 89.82 — 99.72 C 109. Example-109 97.10 — 97.15 B 110.Example-110 47.19 — 95.07 — 111. Example-111 87.20 — 96.15 A 112.Example-112 99.53 — 99.83 A 113. Example-113 99.30 — 99.06 A 114.Example-114 99.06 — 98.39 A 115. Example-115 96.49 — 98.22 A 116.Example-116 97.97 — 95.50 A 117. Example-117 67.93 — 95.02 — 118.Example-118 76.25 — 87.82 C 119. Example-119 88.70 — 94.30 A 120.Example-120 11.45 — 46.01 — 121. Example-121 16.28 — 72.53 — 122.Example-122 92.22 — 93.49 A 123. Example-123 93.78 — 100.00 A 124.Example-124 27.96 — 88.96 — 125. Example-125 79.87 — 94.99 — 126.Example-126 100.00 — 99.29 A 127. Example-127 32.43 — 58.48 — 128.Example-128 91.83 — 89.35 A 129. Example-129 93.50 — 92.14 A 130.Example-130 96.56 — 97.79 B 131. Example-131 100.00 — 99.23 A 132.Example-132 91.76 — 89.83 A 133. Example-133 98.00 — 97.89 A 134.Example-134 91.45 — 93.88 A 135. Example-135 92.26 — 98.89 A 136.Example-136 95.06 — 94.79 A 137. Example-137 93.36 — 93.06 A 138.Example-138 93.30 — 92.91 A 139. Example-139 93.94 — 99.06 A 140.Example-140 97.36 — 98.11 A 141. Example-141 97.57 — 97.48 A 142.Example-142 97.25 — 93.98 A 143. Example-143 99.21 — 90.70 A 144.Example-144 97.49 — 92.73 A 145. Example-145 94.24 — 98.86 A 146.Example-146 100.00 — 99.73 A 147. Example-147 98.64 — 97.61 A 148.Example-148 98.91 — 97.78 A 149. Example-149 98.34 — 94.61 A 150.Example-150 98.38 — 99.52 A 151. Example-151 64.96 — 95.89 — 152.Example-152 96.01 — 100.00 A 153. Example-153 93.94 — 99.65 B 154.Example-154 95.18 — 100.00 A 155. Example-155 99.74 — 97.08 A 156.Example-156 98.50 — 99.25 A 157. Example-157 98.54 — 96.46 A 158.Example-158 99.05 — 99.70 A 159. Example-159 75.40 — 96.76 C 160.Example-160 96.62 — 97.33 A 161. Example-161 98.04 — 99.36 A 162.Example-162 99.35 — 99.33 A 163. Example-163 91.82 — 98.66 A 164.Example-164 98.30 — 97.19 A 165. Example-165 97.91 — 99.51 A 166.Example-166 99.68 — 100.00 A 167. Example-167 99.03 — 98.43 A 168.Example-168 100.00 — 98.89 A 169. Example-169 95.54 — 99.17 C 170.Example-170 99.83 — 98.87 A 171. Example-171 95.22 — 99.60 A 172.Example-172 91.86 — 99.04 C 173. Example-173 96.77 — 98.95 A 174.Example-174 99.90 — 100.00 A 175. Example-175 99.44 — 99.44 A 176.Example-176 45.84 — 89.54 — 177. Example-177 29.89 — 71.07 — 178.Example-178 42.72 — 91.55 — 179. Example-179 50.59 — 95.17 — 180.Example-180 72.34 — 92.51 C 181. Example-181 88.24 — 94.28 A 182.Example-182 92.94 — 94.05 A 183. Example-183 41.55 — 85.5 — 184.Example-184 98.59 — 94.26 A 185. Example-185 96.06 — 98.3 A 186.Example-186 96.84 — 98.02 A 187. Example-187 98.63 — 97.51 A 188.Example-188 89.49 — 99.32 B 189. Example-189 96.17 — 98.48 A 190.Example-190 100 — 100 A 191. Example-191 93.5 — 100 C 192. Example-19299.3 — 99.31 AScreening for mPGES-1 Inhibitors Using the A549 Cell Based Assay

The inhibition of mPGES-1 enzyme in the A549 cell line was monitored asinhibition of IL-1β induced PGE₂ release. A549 cells were maintained inDMEM medium with 10% FBS and 1% Penicillin-Streptomycin Solution in 5%CO₂ at 37° C. Cells were seeded 24 h prior to the assay in 96 wellplates in DMEM containing 1% Penicillin-Streptomycin and 2% FBS so as toget ˜40,000 cells per well on the day of experiment. The assay wascarried out in a total volume of 200 μL. Test compounds were dissolvedin dimethyl sulfoxide (DMSO) to prepare 2 mM stock solution and thendiluted using plain DMEM. The final concentration of DMSO in thereaction was 0.55% (v/v). Cells were treated with test compounds for 30minutes followed by addition of IL-1β at a final concentration of 10ng/mL for 16-20 h. Plates were then centrifuged at 1000 rpm for 10 minat 4° C. Supernatants were collected and analyzed by the addition ofPGE₂-D2 and anti-PGE₂ cryptate conjugate supplied by the CisBio HTRF kitin a 96 well half area Blackwell EIA/RIA plate. The assay plate wasincubated overnight at 4-5° C. before being read in an Artemis (K-101)(Japan) HTRF plate reader and levels of PGE₂ calculated by extrapolationfrom the standard curve.

The concentration response curves were plotted as a percentage ofmaximal response obtained in the absence of test antagonist. The IC₅₀value was calculated from the concentration response curve by nonlinearregression analysis using GraphPad PRISM software.

What is claimed is:
 1. A compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³ and X⁴ are each independently selected from CH and N; each occurrence of L is independently selected from —CH₂NHC(O)— and —CH₂NHS(O)₂—; each occurrence of P is independently selected from —CH₂NHC(O)— and —CH₂NHS(O)₂—; each occurrence of Q is independently selected from C₁₋₈alkyl, haloC₁₋₈alkyl, C₁₋₈alkoxyC₁₋₈alkyl, hydroxyC₁₋₈alkyl, carboxylC₁₋₈alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₄aryl, 3-15 membered heterocyclyl, and 5-14 membered heteroaryl; each occurrence of W is independently selected from C₁₋₈alkyl, haloC₁₋₈alkyl, C₁₋₈alkoxyC₁₋₈alkyl, hydroxyC₁₋₈alkyl, carboxylC₁₋₈alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₄aryl, 3-15 membered heterocyclyl, and 5-14 membered heteroaryl; each occurrence of R¹ is independently selected from halogen, cyano, C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkoxyC₁₋₈alkyl, haloC₁₋₈alkyl, C₃₋₆cycloalkyl, 5 membered heterocyclylC₁₋₈alkyl, 5 membered heteroaryl, 5 membered heteroarylC₁₋₈alkyl, and —C≡CR; each occurrence of R² is independently selected from halogen, cyano, C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl, C₃₋₆cycloalkyl, 5 membered heteroaryl, —C(O)NHR, —NHC(O)R, —S(O)₂NHR and —C≡CR; each occurrence of R is independently selected from C₁₋₈alkyl, C₃₋₁₂cycloalkyl, and C₆₋₁₄aryl; ‘m’ is an integer ranging from 0 to 3, both inclusive; ‘n’ is an integer ranging from 0 to 3, both inclusive; ‘s’ is an integer ranging from 0 to 1, both inclusive; and ‘t’ is an integer ranging from 0 to 1, both inclusive; with the provisos that (i) ‘s’ and ‘t’ are not ‘0’ simultaneously, and (ii) ‘m’ and ‘n’ are not ‘0’ simultaneously.
 2. The compound according to claim 1, wherein X¹, X², X³ and X⁴ are CH.
 3. The compound according to claim 1, wherein each occurrence of R¹ is independently cyano, Cl, F, CHF₂, CF₃, OCH₃, CH₃, (2,2,2-trifluoroethoxy)methyl, cyclopropyl, (pyrrolidin-1-yl)methyl, 4-methylthiophenyl, 5-isopropyl-1,3,4-oxadiazol-2-yl, (3,5-dimethyl-1H-pyrazol-1-yl)methyl, 3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl, (2,5-dichlorophenyl)ethynyl, (4-chloro-2-fluorophenyl)ethynyl, (3-chloro-2-fluorophenyl)ethynyl, (3-(trifluoromethyl)phenyl)ethynyl or (2-chloro-4-(trifluoromethyl)phenyl)ethynyl; and ‘n’ is 1 or
 2. 4. The compound according to claim 1, wherein each occurrence of R² is independently cyano, Cl, F, CH₃, CF₃, OCH₃, 3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl, cyclopropanecarboxamido, 3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl, —CONH-[3-(trifluoromethyl)phenyl], —CONH-[3-(difluoromethyl)-4-fluorophenyl] or —CONH-[3-(difluoromethyl)phenyl]; and ‘m’ is 1 or
 2. 5. The compound according to claim 1, wherein Q is isopropyl, tert-butyl, trifluoromethyl, 1-fluoro-2-methylpropan-2-yl, 1-methoxy-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorophenyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl, (R)-tetrahydrofuran-2-yl, isoxazolyl or 1-methyl-1H-imidazole-2-yl; ‘s’ is 1; and ‘t’ is
 0. 6. The compound according to claim 1, wherein W is isopropyl, tert-butyl, trifluoromethyl, 1-fluoro-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl or cyclopropyl; ‘t’ is 1; and ‘s’ is
 0. 7. The compound according to claim 1 of the formula (III)

or a pharmaceutically acceptable salt thereof, wherein X¹, X² and X³ are each independently selected from CH and N; P is selected from —CH₂NHC(O)— and —CH₂NHS(O)₂—; Q is selected from C₁₋₈alkyl, haloC₁₋₈alkyl, C₁₋₈alkoxyC₁₋₈alkyl, hydroxyC₁₋₈alkyl, carboxylC₁₋₈alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₄aryl, 3-15 membered heterocyclyl, and 5-14 membered heteroaryl; each occurrence of R¹ is independently selected from halogen, cyano, C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl and C₃₋₆cycloalkyl; each occurrence of R² is independently selected from halogen, cyano, C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl, C₃₋₆cycloalkyl, 5 membered heteroaryl, —C(O)NHR, —NHC(O)R, —S(O)₂NHR and —C≡CR; each occurrence of R is independently selected from C₁₋₈alkyl, C₃₋₁₂cycloalkyl, and C₆₋₁₄aryl; ‘m’ is an integer ranging from 0 to 3, both inclusive; and ‘n’ is an integer ranging from 0 to 3, both inclusive; with the proviso that ‘m’ and ‘n’ are not ‘0’ simultaneously.
 8. The compound according to claim 7, wherein X¹, X², and X³ are CH.
 9. The compound according to claim 7, wherein each occurrence of R¹ is independently cyano, Cl, F, CHF₂, CF₃, OCH₃, CH₃ or cyclopropyl and ‘n’ is 1 or
 2. 10. The compound according to claim 7, wherein each occurrence of R² is independently cyano, Cl, F, CH₃, CF₃, OCH₃, 3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl, cyclopropanecarboxamido, 3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl, —CONH-[3-(trifluoromethyl)phenyl], —CONH-[3-(difluoromethyl)-4-fluorophenyl] or —CONH-[3-(difluoromethyl)phenyl]; and ‘m’ is 1 or
 2. 11. The compound according to claim 7, wherein P is —CH₂NHC(O)—.
 12. The compound according to claim 7, wherein Q is isopropyl, tert-butyl, trifluoromethyl, 1-fluoro-2-methylpropan-2-yl, 1-methoxy-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorophenyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl, (R)-tetrahydrofuran-2-yl, isoxazolyl or 1-methyl-1H-imidazole-2-yl.
 13. The compound according to claim 1 of the formula (IV)

or a pharmaceutically acceptable salt thereof, wherein L is selected from —CH₂NHC(O)— and —CH₂NHS(O)₂—; W is selected from C₁₋₈alkyl, haloC₁₋₈alkyl, C₁₋₈alkoxyC₁₋₈alkyl, hydroxyC₁₋₈alkyl, carboxylC₁₋₈alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₄aryl, 3-15 membered heterocyclyl, and 5-14 membered heteroaryl; each occurrence of R¹ is independently selected from halogen, cyano, C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkoxyC₁₋₈alkyl, haloC₁₋₈alkyl, C₃₋₆cycloalkyl, 5 membered heterocyclylC₁₋₈alkyl, 5 membered heteroaryl, 5 membered heteroarylC₁₋₈alkyl, and —C≡CR; each occurrence of R² is independently selected from halogen, cyano, C₁₋₈alkyl, C₁₋₈alkoxy and haloC₁₋₈alkyl; each occurrence of R is independently selected from C₁₋₈alkyl, C₃₋₁₂cycloalkyl, and C₆₋₁₄aryl; ‘m’ is an integer ranging from 0 to 3, both inclusive; and ‘n’ is an integer ranging from 0 to 3, both inclusive; with the proviso that ‘m’ and ‘n’ are not ‘0’ simultaneously.
 14. The compound according to claim 13, wherein each occurrence of R¹ is independently cyano, Cl, F, CHF₂, CF₃, OCH₃, CH₃, (2,2,2-trifluoroethoxy)methyl, (pyrrolidin-1-yl)methyl, 4-methylthiophenyl, 5-isopropyl-1,3,4-oxadiazol-2-yl, (3,5-dimethyl-1H-pyrazol-1-yl)methyl, 3,3-dimethylbut-1-ynyl, 2-cyclopropylethynyl, (2,5-dichlorophenyl)ethynyl, (4-chloro-2-fluorophenyl)ethynyl, (3-chloro-2-fluorophenyl)ethynyl, (3-(trifluoromethyl)phenyl)ethynyl or (2-chloro-4-(trifluoromethyl)phenyl)ethynyl; and ‘n’ is 1 or
 2. 15. The compound according to claim 13, wherein each occurrence of R² is independently cyano, Cl, F, CH₃, CF₃ or OCH₃; and ‘m’ is 1 or
 2. 16. The compound according to claim 13, wherein L is —CH₂NHC(O)—.
 17. The compound according to claim 13, wherein W is isopropyl, tert-butyl, trifluoromethyl, 1-fluoro-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl or cyclopropyl.
 18. The compound according to claim 1 selected from 4-(3-(2-Chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide; N-(4-Chloro-3-(1-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanecarboxamide; 4-(3-(2-Chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide; N-(4-Chloro-3-(1-(4-(cyclopropanecarboxamido)-3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanecarboxamide; 4-(3-(2-Chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)phenyl)-2-methoxybenzamide; 4-(3-(2-Chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(trifluoromethyl)phenyl)benzamide; N-(4-Chloro-3-(3-(4-((2,5-dichlorophenyl)ethynyl)-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide; N-(4-Chloro-3-(3-(4-((4-chloro-2-fluorophenyl)ethynyl)-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide; N-(4-Chloro-3-(3-(2-fluoro-4-((3-(trifluoromethyl)phenyl)ethynyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide; N-(4-Chloro-3-(3-(4-((3-chloro-2-fluorophenyl)ethynyl)-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide; N-(4-Chloro-3-(3-(4-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide; N-(4-Chloro-3-(1-(3,4-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide; N-(4-Chloro-2-fluoro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(2,4-difluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide; N-(4-Chloro-2-fluoro-3-(1-(4-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-2-fluoro-3-(3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(4-Chloro-3-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)pivalamide; N-(4-Chloro-3-(1-(4-cyanophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide; N-(4-Chloro-3-(3-(4-chloro-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)pivalamide; N-(4-Chloro-3-(3-(4-chloro-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide; N-(4-Chloro-3-(3-(2-fluoro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide; N-(4-Chloro-2-fluoro-3-(5-oxo-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(4-Chloro-2-fluoro-3-(5-oxo-1-(5-(trifluoromethyl)pyridin-2-yl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-2-fluoro-3-(5-oxo-1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide; N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide; N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; (R)—N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)tetrahydrofuran-2-carboxamide; N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanesulfonamide; N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2-fluorobenzamide; N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)isoxazole-5-carboxamide; N-(3-(1-(4-(Trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)-2,2,2-trifluoroacetamide; (R)—N-(2,4-Dimethyl-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)tetrahydrofuran-2-carboxamide; N-(3-(1-(4-(Trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)pivalamide; (S)—N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-tetrahydrofuran-2-carboxamide; N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-1-methyl-1H-imidazole-2-carboxamide; N-(4-Chloro-2-fluoro-3-(4,5-dihydro-3-(4-(3,3-dimethylbut-1-ynyl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(4-Chloro-3-(3-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-2-fluorobenzyl)pivalamide; N-(4-Chloro-2-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide; N-(4-Chloro-2-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-3-hydroxy-2,2-dimethylpropanamide; N-(4-Chloro-3-(1-(4-chloro-3-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide; (R)—N-(4-chloro-2-fluoro-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)tetrahydrofuran-2-carboxamide; N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-3-methoxy-2,2-dimethylpropanamide; N-(4-Chloro-3-(1-(4-chloro-3-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide; N-(4-Chloro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-methoxybenzyl)pivalamide; N-(4-Chloro-2-fluoro-5-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-2-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(2,4-Dichloro-5-(3-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(4-Chloro-5-(1-(3-chloro-4-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide; N-(4-Chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-2-fluorobenzamide; N-(4-Chloro-2-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)isobutyramide; N-(4-Chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-3-fluoro-2,2-dimethylpropanamide; N-(4-Chloro-5-(1-(3-chloro-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide; N-(4-Chloro-5-(3-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-2-fluorobenzyl)pivalamide; N-(4-Chloro-2-fluoro-5-(4,5-dihydro-3-(4-(3,3-dimethylbut-1-ynyl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(3-chloro-4-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(3-chloro-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(3-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(4,5-dihydro-3-(4-(3,3-dimethylbut-1-ynyl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide; N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)isobutyramide; N-(4-Chloro-3-(3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(4-Chloro-3-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(4-Chloro-3-(3-(4-chloro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(4-Chloro-3-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(4-Chloro-3-(3-(3-fluoro-4-(3,3-dimethylbut-1-ynyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide; N-(4-Chloro-3-(3-(4-(2-cyclopropylethynyl)-3-fluorophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide; N-(4-Chloro-3-(4,5-dihydro-5-oxo-3-(4-((pyrrolidin-1-yl)methyl)phenyl)-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(3-(3-(4-((2,2,2-Trifluoroethoxy)methyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-4-chlorobenzyl)pivalamide; N-(4-Chloro-3-(4,5-dihydro-3-(4-(5-isopropyl-1,3,4-oxadiazol-2-yl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(4-chloro-3-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(4-chloro-3-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)isobutyramide; N-(4-Chloro-3-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(4-chloro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(3-(trifluoromethyl)-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(4-(trifluoromethyl)-2-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)isobutyramide; N-(4-Chloro-3-{5-oxo-1-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}benzyl)propane-2-sulfonamide; N-(4-Chloro-3-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(3-(4,5-Dihydro-1-(4-(3,3-dimethylbut-1-ynyl)phenyl)-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)isobutyramide; N-(3-(1-(4-(2-Cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)pivalamide; N-(4-Chloro-3-(3-(4-(2-cyclopropylethynyl)-3-fluorophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(4-(2-cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(3-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(3-(1-(4-(2-Cyclopropylethynyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)-3-fluoro-2,2-dimethylpropanamide; N-(3-(1-(3-Fluoro-4-(3,3-dimethylbut-1-ynyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)isobutyramide; N-(4-Chloro-3-(4,5-dihydro-3-(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)phenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide; N-(4-Chloro-2-fluoro-3-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(1-(4-chloro-3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)pivalamide; N-(4-Chloro-3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-3-fluoro-2,2-dimethylpropanamide; N-((6-Cyclopropyl-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)pivalamide; N-(4-Chloro-3-(1-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)pivalamide; N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2-methylpropane-2-sulfonamide; N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclobutanecarboxamide; N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopentanecarboxamide; N-((6-(Difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)pivalamide; N-((6-(Difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)isobutyramide; N-((6-(Difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)propane-2-sulfonamide; N-((6-(Difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclobutanecarboxamide; N-(4-Chloro-3-(3-(4-(cyclopropylethynyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide; N-(4-Chloro-3-(3-(4-(cyclopropylethynyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-3-hydroxy-2,2-dimethylpropanamide; 3-Fluoro-N-((6-(difluoromethyl)-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)-2,2-dimethylpropanamide; and pharmaceutically acceptable salts thereof.
 19. A compound of the formula

or a pharmaceutically acceptable salt thereof.
 20. A compound of the formula

or a pharmaceutically acceptable salt thereof.
 21. A compound of the formula

or a pharmaceutically acceptable salt thereof.
 22. A compound selected from 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one; N-(4-Chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide; N-(4-Chloro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide; and pharmaceutically acceptable salts thereof.
 23. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable excipient.
 24. The pharmaceutical composition according to claim 23, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
 25. A method of relieving a mPGES-1 mediated disease, disorder or syndrome in a subject comprising administering to a subject having said disease, disorder or syndrome an effective amount of a compound according to claim
 1. 26. A pharmaceutical composition comprising a compound according to claim 19, and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof.
 27. A pharmaceutical composition comprising a compound according to claim 20, and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof.
 28. A process for preparing a compound of formula (II)

or a pharmaceutically acceptable salt thereof, which comprises: reacting a compound of formula (Intermediate-IIA*) with a compound of formula (Intermediate-IIB*) to form a compound of formula (Intermediate-IIC*); and converting the compound of formula (Intermediate-IIC*) to a compound of formula (II):

wherein, X¹, X², X³ and X⁴ are each independently selected from CH and N; each occurrence of L is independently selected from —CH₂NHC(O)— and —CH₂NHS(O)₂—; each occurrence of P is independently selected from —CH₂NHC(O)— and —CH₂NHS(O)₂—; each occurrence of Q is independently selected from C₁₋₈alkyl, haloC₁₋₈alkyl, C₁₋₈alkoxyC₁₋₈alkyl, hydroxyC₁₋₈alkyl, carboxylC₁₋₈alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₄aryl, 3-15 membered heterocyclyl, and 5-14 membered heteroaryl; each occurrence of W is independently selected from C₁₋₈alkyl, haloC₁₋₈alkyl, C₁₋₈alkoxyC₁₋₈alkyl, hydroxyC₁₋₈alkyl, carboxylC₁₋₈alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₄aryl, 3-15 membered heterocyclyl, and 5-14 membered heteroaryl; each occurrence of R¹ is independently selected from halogen, cyano, C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkoxyC₁₋₈alkyl, haloC₁₋₈alkyl, C₃₋₆cycloalkyl, 5 membered heterocyclylC₁₋₈alkyl, 5 membered heteroaryl, 5 membered heteroarylC₁₋₈alkyl, and —C≡CR; each occurrence of R² is independently selected from halogen, cyano, C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl, C₃₋₆cycloalkyl, 5 membered heteroaryl, —C(O)NHR, —NHC(O)R, —S(O)₂NHR and —C≡CR; each occurrence of R is independently selected from C₁₋₈alkyl, C₃₋₁₂cycloalkyl, and C₆₋₁₄aryl; PG¹ represents an amine protecting group; ‘m’ is an integer ranging from 0 to 3, both inclusive; ‘n’ is an integer ranging from 0 to 3, both inclusive; ‘s’ is an integer ranging from 0 to 1, both inclusive; and ‘t’ is an integer ranging from 0 to 1, both inclusive; with the provisos that (i) ‘s’ and ‘t’ are not ‘0’ simultaneously; and (ii) that ‘m’ and ‘n’ are not ‘0’ simultaneously.
 29. The process according to claim 28, wherein the isocyanate of formula (Intermediate-IIA*) is obtained from the corresponding acid, amide or acid halide derivative.
 30. The process according to claim 28, wherein a compound of formula (Intermediate-IIA*) is reacted with a compound of formula (Intermediate-IIB*) in DCM, toluene or EDC.
 31. The process according to claim 28, wherein Intermediate-IIC* is not isolated.
 32. The process according to claim 28, wherein Intermediate-IIC* is isolated.
 33. The process according to claim 28, wherein PG¹ is tert-butoxycarbonyl.
 34. The process according to claim 28, wherein a compound of formula (Intermediate-IIC*) is converted to compound of formula (II) using an acid.
 35. The process according to claim 34, wherein the acid is an organic acid.
 36. A method of relieving a mPGES-1 mediated disease, disorder or syndrome in a subject comprising administering to a subject having such disease, disorder or syndrome an effective amount of a compound according to claim
 19. 